Amine functional polyamides

ABSTRACT

Amine functional polyamides comprise amine and ammonium groups along the polymer chain. Amine functional polyamides can be used as pharmaceutical agents and in pharmaceutical compositions. The amine functional polyamides are particularly useful in the treatment or prevention of mucositis and infection, specifically oral mucositis, surgical site infection, and lung infection associated with cystic fibrosis.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

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THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT

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INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON COMPACT DISC

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BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to amine functional polyamides. Amine functionalpolyamides comprise amine and ammonium groups along the polymer chain.This invention further relates to the use of amine functional polyamidesas pharmaceutical agents and in pharmaceutical compositions.

Mucositis is defined as inflammation and/or ulceration of a mucousmembrane in the digestive tract. Mucositis can occur in the stomach,intestines and mouth. The disorder is characterized by breakdown ofmucosa, which results in redness, swelling and/or the formation ofulcerative lesions.

Oral mucositis is a common dose-limiting toxicity of drug and radiationtherapy for cancer; it occurs to some degree in more than one third ofall patients receiving anti-neoplastic drug therapy. In granulocytopenicpatients, the ulcerations that accompany mucositis are frequent portalsof entry for indigenous oral bacteria leading to sepsis or bacteremia.There are about one million occurrences of oral mucositis annually inthe United States. Mucositis also includes mucositis that developsspontaneously in a healthy patient not receiving ant-cancer therapy, asin the case of a canker sore or mouth ulcer. Improved therapies to treatmucositis are needed.

Surgical site infection (SSI) is an infection associated with a surgicalprocedure. Postoperative SSIs are a major source of illness, and lesscommonly death, in surgical patients (Nichols R L, 2001). The Guidelinefor Prevention of Surgical Site Infection (1999) sets forthrecommendations for preventing SSIs.

-   -   Preoperative measures including proper preparation of the        patient, antisepsis for surgical team, management of surgical        personnel who exhibit signs of transmissible infectious illness,        and antimicrobial prophylaxis.    -   Intra-operative measures including proper ventilation in the        operating room, cleaning and disinfecting of surfaces in the        surgical environment, microbiologic sampling, sterilization of        surgical instruments, proper surgical attire and drapes, and        proper asepsis and surgical technique.    -   Proper incision care post-operation, including sterile dressings        and hand washing before and after dressing changes.    -   Continued surveillance of the surgical wound during the healing        process.

Despite these recommendations, SSIs develop in about 1 to 3 of every 100patients who have surgery (CDC.gov, 2011). These infections can resultin major complications that increase the costs and duration ofpost-operative hospital stays. Accordingly, novel approaches tomitigating SSIs are needed.

Cystic fibrosis (CF) is a genetic disease caused by a mutation in thecystic fibrosis transmembrane conductor regulator (CFTR) that results inabnormally thick and sticky mucus (Yu Q, et al., 2012). The thick,sticky mucus of a CF patient leads to compromised mucus clearance andlung infection. Chronic airway infections are one of the most common anddebilitating manifestations of CF (Tümmler B and C Kiewitz, 1999). Thestagnant mucus becomes a breeding ground for bacteria like Pseudomonasaeruginosa, which causes chronic airway infections (Moreau-Marquis S, GA O'Toole and B A Stanton, 2009). Despite the use of traditionalantibacterial therapies in CF patients, most CF patients are afflictedwith a chronic P. aeruginosa infection as teenagers and adults, leadingto increased morbidity and mortality (Hoiby N, B Frederiksen B, TPressler, 2005). In chronic P. aeruginosa infection, the P. aeruginosaforms biofilms, resulting in a greater tolerance to antibiotics andincreasing difficulty in treatment (Yu Q, et al., 2012). Effective,novel treatments to assuage the effects of bacterial infection andbiofilm formation in CF patients are needed.

DEFINITIONS

As used herein, the term “amino” means a functional group having anitrogen atom and 1 to 2 hydrogen atoms. “Amino” generally may be usedherein to describe a primary, secondary, or tertiary amine, and those ofskill in the art will readily be able to ascertain the identification ofwhich in view of the context in which this term is used in the presentdisclosure. The term “amine” or “amine group” or “ammonia group” means afunctional group containing a nitrogen atom derived from ammonia (NH₃).The amine groups may be primary amines, meaning the nitrogen is bondedto two hydrogen atoms and one substituent group comprising a substitutedor unsubstituted alkyl or aryl group or an aliphatic or aromatic group.The amine groups may be secondary amines meaning, the nitrogen is bondedto one hydrogen atom and two substituent groups comprising a substitutedor unsubstituted aklyl or aryl groups or an aliphatic or aromatic group,as defined below. The amine groups may be tertiary amines meaning thenitrogen is bonded to three substituent groups comprising a substitutedor unsubstituted aklyl or aryl groups or an aliphatic or aromatic group.The amine groups may also be quaternary amines meaning the designatedamine group is bonded to a fourth group, resulting in a positivelycharged ammonium group.

As used herein, the term “amide group” means a functional groupcomprising a carbonyl group linked to a nitrogen. A “carbonyl group”means a functional group comprising a carbon atom double bonded to anoxygen atom, represented by (C═O).

The term “alkane” means a saturated hydrocarbon, bonded by single bonds.Alkanes can be linear or branched. “Cycloalkanes” are saturatedhydrocarbons rings bonded by single bonds.

As used herein, the term “(C₁-C₁₀)alkyl” means a saturated straightchained or branched or cyclic hydrocarbon consisting essentially of 1 to10 carbon atoms and a corresponding number of hydrogen atoms. Typicallystraight chained or branched groups have from one to ten carbons, ormore typically one to five carbons. Exemplary (C₁-C₁₀)alkyl groupsinclude methyl (represented by —CH₃), ethyl (represented by —CH₂—CH₃),n-propyl, isopropyl, n-butyl, isobutyl, etc. Other (C₁-C₁₀)alkyl groupswill be readily apparent to those of skill in the art given the benefitof the present disclosure.

As used herein, the term “(C₂-C₉)heteroalkyl” means a saturated straightchained or branched or cyclic hydrocarbon consisting essentially of 2 to10 atoms, wherein 2 to 9 of the atoms are carbon and the remainingatom(s) is selected from the group consisting of nitrogen, sulfur, andoxygen. Exemplary (C₂-C₉)heteroalkyl groups will be readily apparent tothose of skill in the art given the benefit of the present disclosure.

As used herein, the term “(C₃-C₁₀)cycloalkyl” means a nonaromaticsaturated hydrocarbon group, forming at least one ring consistingessential of 3 to 10 carbon atoms and a corresponding number of hydrogenatoms. (C₃-C₁₀)cycloalkyl groups can be monocyclic or multicyclic.Individual rings of multicyclic cycloalkyl groups can have differentconnectivities, for example, fused, bridged, spiro, etc., in addition tocovalent bond substitution. Exemplary (C₃-C₁₀)cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomanyl,bicyclo-octanyl, octahydro-pentalenyl, spiro-decanyl, cyclopropylsubstituted with cyclobutyl, cyclobutyl substituted with cyclopentyl,cyclohexyl substituted with cyclopropyl, etc. Other (C₃-C₁₀)cycloalkylgroups will be readily apparent to those of skill in the art given thebenefit of the present disclosure.

As used herein, the term “(C₂-C₉)heterocycloalkyl” means a nonaromaticgroup having 3 to 10 atoms that form at least one ring, wherein 2 to 9of the ring atoms are carbon and the remaining ring atom(s) is selectedfrom the group consisting of nitrogen, sulfur, and oxygen.(C₂-C₉)heterocycloalkyl groups can be monocyclic or multicyclic.Individual rings of such multicyclic heterocycloalkyl groups can havedifferent connectivities, for example, fused, bridged, spiro, etc., inaddition to covalent bond substitution. Exemplary(C₂-C₉)heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl,dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl,azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, piperizin-2-onyl, piperizin-3-onyl,chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl,1,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl,3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl,2,5-diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[1,2-a]pyrazinyl,3-azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.1.0]hexanyl,2-azaspiro[4.4]nonanyl, 7-oxa-1-aza-spiro[4.4]nonanyl,7-azabicyclo[2.2.2]heptanyl, octahydro-1H-indolyl, etc. The(C₂-C₉)heterocycloalkyl group is typically attached to the mainstructure via a carbon atom or a nitrogen atom. Other(C₂-C₉)heterocycloalkyl groups will be readily apparent to those ofskill in the art given the benefit of the present disclosure.

The term “aliphatic group” or “aliphatic” means a non-aromatic groupconsisting of carbon and hydrogen, and may optionally include one ormore double and/or triple bonds. An aliphatic group may be straightchained, branched or cyclic and typically contains between about one andabout 24 carbon atoms.

The term “aryl group” may be used interchangeably with “aryl,” “arylring,” “aromatic,” “aromatic group,” and “aromatic ring.” Aryl groupsinclude carbocyclic aromatic groups, typically with six to fourteen ringcarbon atoms. Aryl groups also include heteroaryl groups, whichtypically have five to fourteen ring atoms with one or more heteroatomsselected from nitrogen, oxygen and sulfur.

As used herein, the term “(C₆-C₁₄)aryl” means an aromatic functionalgroup having 6 to 14 carbon atoms that form at least one ring.

As used herein, the term “(C₂-C₉)heteroaryl” means an aromaticfunctional group having 5 to 10 atoms that form at least one ring,wherein 2 to 9 of the ring atoms are carbon and the remaining ringatom(s) is selected from the group consisting of nitrogen, sulfur, andoxygen. (C₂-C₉)heteroaryl groups can be monocyclic or multicyclic.Individual rings of such multicyclic heteroaryl groups can havedifferent connectivities, for example, fused, etc., in addition tocovalent bond substitution. Exemplary (C₂-C₉)heteroaryl groups includefuryl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl,1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl,purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl,5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl and benzoxazinyl, etc. The (C₂-C₉)heteroarylgroup is typically attached to the main structure via a carbon atom,however, those of skill in the art will realize when certain otheratoms, for example, hetero ring atoms, can be attached to the mainstructure. Other (C₂-C₉)heteroaryl groups will be readily apparent tothose of skill in the art given the benefit of the present disclosure.

As used herein, the term “alkyl amine” means an (C₁-C₁₀)alkyl containinga primary, secondary, or tertiary amine group in place of one hydrogenatom, represented by (C₁-C₁₀)alkyl amine and ((C₁-C₁₀)alkyl)₂ amine.

The term “alkyl ester” means a (C₁-C₁₀)alkyl containing an ester groupin place of one hydrogen atom, represented by —O(O)C—(C₁-C₁₀)alkyl.

The term “alkyl acid” means an (C₁-C₁₀)alkyl containing a carboxylicacid group in place of one hydrogen atom, represented by(C₁-C₁₀)alkyl-COOH.

The term “aliphatic acid” means an acid of nonaromatic hydrocarbons,represented by (C₃-C₁₀)cycloalkyl-COOH.

The term “halo” means a fluorine (F), chlorine (Cl), bromine (Br),iodine (I), or astatine (At) ion.

The term “methoxy” means a (C₁)alkyl containing an oxygen in place ofone hydrogen atom, represented by —(O)CH₃.

The term “polyol” means an alcohol containing multiple hydroxyl (—OH)groups.

“Substituted” means the substitution of a carbon in alkyl, heterocyclicor aryl groups with one or more non-carbon substituent. Non-carbonsubstituents are selected from nitrogen, oxygen and sulfur.

“Unsubstituted” means the group is comprised of only hydrogen andcarbon.

The term “polymer” means a molecule comprised of repeating units. Theterm “repeat unit” or “monomer” means a group in a polymer that repeatsor appears multiple times in a polymer. A polymer may be a copolymer ifthe repeating units or “comonomers” are chemically and structurallydifferent from one another.

The term “pharmaceutically acceptable anion” means an anion that issuitable for pharmaceutical use. Pharmaceutically acceptable anionsinclude but are not limited to halides, carbonate, bicarbonate, sulfate,bisulfate, hydroxide, nitrate, persulfate, sulfite, acetate, ascorbate,benzoate, citrate, dihydrogen citrate, hydrogen citrate, oxalate,succinate, tartrate, taurocholate, glycocholate, and cholate.

The term “pharmaceutically acceptable end group” means an end group thatis suitable for pharmaceutical use. Examples of pharmaceuticallyacceptable end groups include but are not limited to H, (C₁-C₁₀)alkyl,(C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,(C₆-C₁₄)aryl, (C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine,—O(O)C—(C₁-C₁₀)alkyl, (C₁-C₁₀)alkyl-COOH, (C₃-C₁₀)cycloalkyl-COOH,—(O)CH₃, —OH, amide, a guanidino group, a guanidinium chloride group, aguanidinobenzene group, a dihydroxy group, and a polyethylene glycolgroup.

A “guanidino group” is represented by Formula (A):

wherein a is an integer from 0 to 25,

A “guanidinium chloride group” is represented by Formula (B),

wherein b is an integer from 0 to 25,

A “guanidinobenzene group” is represented by Formula (C),

wherein c is an integer from 0 to 25,

A “dihydroxy group” is represented by Formula (D),

wherein d is an integer from 0 to 25, or

A “polyethylene glycol group” is represented by Formula (E)

wherein e is an integer from 1 to 400.

The term “effective amount” of a disclosed amine functional polyamidesis a quantity sufficient to achieve a therapeutic and/or prophylacticeffect on the particular condition being treated, such as an amountwhich results in the prevention or a decrease in the symptoms associatedwith mucositis, oral mucositis, infection and surgical site infection,and lung infection associated with cystic fibrosis. The precise amountof the disclosed amine functional polyamides that is administered willdepend on the type and severity of mucositis or infection being treatedand on the characteristics of the individual, such as general health,age, sex, body weight and tolerance to drugs.

RELATED ART

Not applicable

BRIEF SUMMARY OF THE INVENTION

In one aspect of the invention, the amine functional polyamides are acompound comprising the structure of Formula (I):

-   -   wherein:    -   i) m is 0, 1, 2, or 3;    -   ii) n is 0, 1, 2, or 3;    -   iii) o is 0, 1, 2, or 3;    -   iv) p is 0 or 1;    -   v) r is 0 or 1;    -   vi) q is an integer from 1 to 400;    -   vii) Q^(x) is NH, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,        (C₂-C₉)heteroaryl;    -   viii) Q^(y) is NH—R^(w), (C₁-C₁₀)alkyl, or (C₆-C₁₄)aryl, wherein        R^(w) is absent or a (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₆-C₁₄)aryl, or (C₂-C₉)heteroaryl;    -   ix) R^(x) and R^(y) are each independently a pharmaceutically        acceptable end group.

In another aspect of the invention, the amine functional polyamides area compound comprising the structure of Formula (II):

-   -   wherein:    -   i) m is 0, 1, 2, or 3;    -   ii) n is 0, 1, 2, or 3;    -   iii) o is 0, 1, 2, or 3;    -   iv) p is 0 or 1;    -   v) r is 0 or 1;    -   vi) q is an integer from 1 to 400;    -   vii) Q^(x) is NH, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,        (C₂-C₉)heteroaryl;    -   viii) Q^(y) is NH—R^(w), NH—CH₂—R_(w), (C₁-C₁₀)alkyl, or        (C₆-C₁₄)aryl, wherein R^(w) is absent or a (C₁-C₁₀)alkyl,        (C₂-C₉)heteroalkyl, (C₆-C₁₄)aryl, or (C₂-C₉)heteroaryl;    -   ix) R^(x) and R^(y) are each independently a pharmaceutically        acceptable end group;    -   x) X⁻ is each independently a halo or any pharmaceutically        acceptable anion;    -   xi) Y¹ and Y² are each independently H or (C₁-C₁₀)alkyl        optionally substituted by one or more substituents selected from        the group consisting of (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₁-C₁₄)aryl,        (C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, —O(O)C—(C₁-C₁₀)alkyl,        —(C₁-C₁₀)alkyl-COOH, (C₃-C₁₀)cycloalkyl-COON, —(O)CH₃, —OH,        amide, a dihydroxy group, represented by Formula (D),

-   -   -   wherein d is an integer from 0 to 25, or

    -   a polyethylene glycol group, represented by Formula (E)

-   -   -   wherein e is an integer from 1 to 25.

In yet another aspect of the invention, the amine functional polyamidesare a compound comprising the structure of Formula (III):

-   -   wherein:    -   i) m is 0, 1, 2, or 3;    -   ii) n is 0, 1, 2, or 3;    -   iii) o is 0, 1, 2, or 3;    -   iv) p is 0 or 1;    -   v) r is 0 or 1;    -   vi) q is an integer from 1 to 400;    -   vii) Q^(x) is NH, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₁-C₁₀)aryl,        (C₂-C₉)heteroaryl;    -   viii) Q^(y) is NH—R^(w), NH—CH₂—R_(w), (C₁-C₁₀)alkyl, or        (C₆-C₁₄)aryl, wherein R^(w) is absent or a (C₁-C₁₀)alkyl,        (C₂-C₉)heteroalkyl, (C₆-C₁₄)aryl, or (C₂-C₉)heteroaryl;    -   i) R^(x) and R^(y) are each independently a pharmaceutically        acceptable end group;    -   ix) X⁻ is a halo or any pharmaceutically acceptable anion;    -   x) Y¹ is H or (C₁-C₁₀)alkyl optionally substituted by one or        more substituents selected from the group consisting of        (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,        (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,        (C₁-C₁₀)alkylamine, —S—O—(C₁-C₁₀)alkyl, —O(O)C—(C₁-C₁₀)alkyl,        —(C₁-C₁₀)alkyl-COOH, (C₃-C₁₀)cycloalkyl-COOH, —(O)CH₃, —OH,        amide, a dihydroxy group, represented by Formula (D),

-   -   -   wherein d is an integer from 0 to 25, or

    -   a polyethylene glycol group, represented by Formula (E),

-   -   -   wherein e is an integer from 1 to 400.

In another aspect of the invention, the amine functional polyamides area compound comprising the structure of Formula (IV):

-   -   wherein:    -   i) u is 0, 1, 2, or 3;    -   ii) v is 0, 1, 2, or 3;    -   iii) q is an integer from 1 to 400;    -   iv) Q^(x) is NH, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,        (C₂-C₉)heteroaryl;    -   v) Q^(y) is NH—R^(w), NH—CH₂—R_(w), (C₁-C₁₀)alkyl, or        (C₆-C₁₄)aryl, wherein R^(w) is absent or a (C₁-C₁₀)alkyl,        (C₂-C₉)heteroalkyl, (C₁-C₁₄)aryl, or (C₂-C₉)heteroaryl;    -   vi) R^(x) and R^(y) are each independently a pharmaceutically        acceptable end group.

In yet another aspect of the invention, the amide functional polyamidesare a compound comprising the structure of Formula (V):

-   -   wherein:    -   i) u is 0, 1, 2, or 3;    -   ii) v is 0, 1, 2, or 3;    -   iii) q is an integer from 1 to 400;    -   iv) Q^(x) is NH, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,        (C₂-C₉)heteroaryl;    -   v) Q^(y) is NH—R^(w), NH—CH₂—R_(w), (C₁-C₁₀)alkyl, or        (C₆-C₁₄)aryl, wherein R^(w) is absent or a (C₁-C₁₀)alkyl,        (C₂-C₉)heteroalkyl, (C₆-C₁₄)aryl, or (C₂-C₉)heteroaryl;    -   vi) R^(x) and R^(y) are each independently a pharmaceutically        acceptable end group;    -   vii) X⁻ is independently a halo or any pharmaceutically        acceptable anion,    -   viii) Y¹ and Y² are independently H or (C₁-C₁₀)alkyl optionally        substituted by one or more substituents selected from the group        consisting of (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,        (C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, —O(O)C—(C₁-C₁₀)alkyl,        —(C₁-C₁₀)alkyl-COOH, (C₃-C₁₀)cycloalkyl-COOH, —(O)CH₃, —OH,        amide, a dihydroxy group, represented by Formula (D),

-   -   -   wherein d is an integer from 0 to 25, or

    -   a polyethylene glycol group, represented by Formula (E)

-   -   -   wherein e is an integer from 1 to 400.

In one aspect of the invention, the amine functional polyamides are apharmaceutical composition comprising a compound comprising thestructure of Formula (I). In another aspect of the invention, aminefunctional polyamides are a pharmaceutical composition comprising acompound comprising the structure of Formula (II). In yet another aspectof the invention, amine functional polyamides are a pharmaceuticalcomposition comprising a compound comprising the structure of Formula(III). In another aspect of the invention, amine functional polyamidesare a pharmaceutical composition comprising a compound comprising thestructure of Formula (IV). In another aspect of the invention, aminefunctional polyamides are a pharmaceutical composition comprising acompound comprising the structure of Formula (V).

In one aspect of the invention, the amine functional polyamides are usedfor the treatment of mucositis. In another aspect of the invention, theamine functional polyamides are used for the treatment of oralmucositis. In another embodiment of the invention, the amine functionalpolyamides are used for the treatment of an infection. In yet anotherembodiment of the invention, the amine functional polyamides are usedfor the treatment of surgical site infection. In another embodiment ofthe invention, the amine functional polyamides are used for thetreatment of lung infection associated with cystic fibrosis. In anotherembodiment of the invention, the amine functional polyamides are usedfor the treatment of P. aeruginosa lung infections in CF patients. Inyet another embodiment of the invention, the amine functional polyamidesare used for the treatment of P. aeruginosa lung infections in CFpatients where biofilms have formed. Yet another aspect of the inventionis a method of treating a condition selected from mucositis, oralmucositis, and infection comprising administering an amine functionalpolyamide.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 shows a comparison of the susceptibility of PseudomonasAeruginosa present in biofilm of cystic fibrosis-derived human airwayepithelial cells of representative amine functional polyamide. Thecolumns (left to right) show the mean log₁₀ CFU (colony forming units)observed for untreated control cystic fibrosis bronchial epithelial(CFBE) cells, CFBE cells treated with 50 μg/mL tobramycin, CFBE cellstreated with 50 μg/mL poly(4,4-trimethylene dipiperidinebisporpanoicacid-diaminopropane), and CFBE cells treated with 500 μg/mLpoly(4,4-trimethylene dipiperidinebisporpanoic acid-diaminopropane)according to the in vitro study described in Example 1-5.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel amine functional polyamides. The aminefunctional polyamides polymers or copolymers and are of varyingstructures and comprise amine and ammonium groups along the polymerchain.

The amine functional polyamides contain repeat units of amide groups andamine groups; the amine groups can be secondary, tertiary, andquaternary ammonium groups.

Further, the amine functional polyamides of the present invention are ofvarying molecular weights.

The amine functional polyamides are water soluble.

This invention relates to pharmaceutical compositions comprisingpolymers or copolymers of amine functional polyamides. This inventionalso relates to methods of treating and preventing mucositis andinfection, including SSI, lung infections in CF patients, and C.aeruginosa lung infections in CF patients with or without biofilmformation, with amine functional polyamides. The amine functionalpolyamides and the pharmaceutical compositions comprising polymers orcopolymers of amine functional polyamides can be administered inmultiple dosage forms and for systemic or local administration.

This invention relates to the use of amine functional polyamides andpharmaceutical compositions comprising polymers or copolymers of aminefunctional polyamides as anti-infective agents. The amine functionalpolyamides and pharmaceutical compositions comprising polymers orcopolymers of amine functional polyamides can be used for the treatmentof bacterial, fungal, and viral infections, including mucositis,infections and, specifically, surgical site infections, lung infectionsassociated with CF, and C. aeruginosa lung infections in CF patientswith or without biofilm formation.

The amine functional polyamides can also be used to coat surfaces ofvarious biomedical devices and other surfaces to prevent infection.

In one aspect of the invention, the amine functional polyamides are acompound comprising the structure of Formula (I):

-   -   wherein:    -   i) m is 0, 1, 2, or 3;    -   ii) n is 0, 1, 2, or 3;    -   iii) o is 0, 1, 2, or 3;    -   iv) p is 0 or 1;    -   v) r is 0 or 1;    -   vi) q is an integer from 1 to 400;    -   vii) Q^(x) is NH, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,        (C₂-C₉)heteroaryl;    -   viii) Q^(y) is NH—R_(w), (C₁-C₁₀)alkyl, or (C₆-C₁₄)aryl, wherein        R^(w) is absent or a (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₆-C₁₄)aryl, or (C₂-C₉)heteroaryl;    -   ix) R^(x) and R^(y) are each independently a pharmaceutically        acceptable end group.

In another aspect of the invention, the amine functional polyamides area compound comprising the structure of Formula (II):

-   -   wherein:    -   i) m is 0, 1, 2, or 3;    -   ii) n is 0, 1, 2, or 3;    -   iii) o is 0, 1, 2, or 3;    -   iv) p is 0 or 1;    -   v) r is 0 or 1;    -   vi) q is an integer from 1 to 400;    -   vii) O^(x) is NH, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,        (C₂-C₉)heteroaryl;    -   viii) Q^(y) is NH—R^(w), NH—CH₂—R_(w), (C₁-C₁₀)alkyl, or        (C₆-C₁₄)aryl, wherein R^(w) is absent or a (C₁-C₁₀)alkyl,        (C₂-C₉)heteroalkyl, (C₆-C₁₄)aryl, or (C₂-C₉)heteroaryl;    -   ix) R^(x) and R^(y) are each independently a pharmaceutically        acceptable end group;    -   x) X⁻ is each independently a halo or any pharmaceutically        acceptable anion;    -   xi) Y¹ and Y₂ are each independently H or (C₁-C₁₀)alkyl        optionally substituted by one or more substituents selected from        the group consisting of (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,        (C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, —O(O)C—(C₁-C₁₀)alkyl,        —(C₁-C₁₀)alkyl-COOH, (C₃-C₁₀)cycloalkyl-COOH, —(O)CH₃, —OH,        amide, a dihydroxy group, represented by Formula (D),

-   -   -   wherein d is an integer from 0 to 25, or

    -   a polyethylene glycol group, represented by Formula (E)

-   -   -   wherein e is an integer from 1 to 25.

In yet another aspect of the invention, the amine functional polyamidesare a compound comprising the structure of Formula (III)

-   -   wherein:    -   i) m is 0, 1, 2, or 3;    -   ii) n is 0, 1, 2, or 3;    -   iii) o is 0, 1, 2, or 3,    -   iv) p is 0 or 1;    -   v) r is 0 or 1;    -   vi) q is an integer from 1 to 400;    -   vii) Q^(x) is NH, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,        (C₂-C₉)heteroaryl;    -   viii) Q^(y) is NH—R^(w), NH—CH₂—R_(w), (C₁-C₁₀)alkyl, or        (C₅-C₁₄)aryl, wherein R^(w) is absent or a (C₁-C₁₀)alkyl,        (C₂-C₉)heteroalkyl, (C₆-C₁₄)aryl, or (C₂-C₉)heteroaryl;    -   ii) R^(x) and R^(y) are each independently a pharmaceutically        acceptable end group;    -   ix) X⁻ is a halo or any pharmaceutically acceptable anion;    -   x) Y¹ is H or (C₁-C₁₀)alkyl optionally substituted by one or        more substituents selected from the group consisting of        (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,        (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,        (C₁-C₁₀)alkylamine, —S—O—(C₁-C₁₀)alkyl, —O(O)C—(C₁-C₁₀)alkyl,        —(C₁-C₁₀)alkyl-COOH, (C₃-C₁₀)cycloalkyl-COOH, —(O)CH₃, —OH,        amide, a dihydroxy group, represented by Formula (D),

-   -   -   wherein d is an integer from 0 to 25, or

    -   a polyethylene glycol group, represented by Formula (E),

-   -   -   wherein e is an integer from 1 to 400.

In preferred embodiments of the invention, the amine functionalpolyamides of are compounds of Formula (I), Formula (II) or Formula(III) where p and r are both 0 and p and r are both 1. In otherpreferred embodiments of the invention, the amine functional polyamidesof are compounds of Formula (I), Formula (II) or Formula (III) where n,p and r are all 0, n is 0 and p and r are both 1, and n is 3 and p and rare both 1.

In a preferred embodiment of the invention, the amide functionalpolyamides are a compound comprising the structure of Formula (1).

-   -   wherein R^(w) is a (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₆-C₁₄)aryl, or (C₂-C₉)heteroaryl.

In another preferred embodiment of the invention, the amide functionalpolyamides are a compound comprising the structure of Formula (2) orFormula (3):

In yet another preferred embodiment of the invention, the aminefunctional polyamides are comprised of a compound comprising thestructure of Formula (I), Formula (II), Formula (III), Formula (1),Formula (2) or Formula (3), wherein R^(x) and R^(y) are independentlyselected from a methoxy group, a guanidino group, or a guanidinobenzenegroup.

In another aspect of the invention, the amine functional polyamides area compound comprising the structure of Formula (IV):

-   -   wherein:    -   i) u is 0, 1, 2, or 3;    -   ii) v is 0, 1, 2, or 3;    -   iii) q is an integer from 1 to 400;    -   iv) Q^(x) is NH, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,        (C₂-C₉)heteroaryl;    -   v) Q^(y) is NH—R^(w), NH—CH₂—R_(w), (C₁-C₁₀)alkyl, or        (C₆-C₁₄)aryl, wherein R^(w) is absent or a (C₁-C₁₀)alkyl,        (C₂-C₉)heteroalkyl, (C₆-C₁₄)aryl, or (C₂-C₉)heteroaryl;    -   vii) R^(x) and R^(y) are each independently a pharmaceutically        acceptable end group.

In yet another aspect of the invention, the amide functional polyamidesare a compound comprising the structure of Formula (V):

-   -   wherein:    -   i) u is 0, 1, 2, or 3;    -   ii) v is 0, 1, 2, or 3;    -   iii) q is an integer from 1 to 400;    -   iv) Q^(x) is NH, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,        (C₂-C₉)heteroaryl;    -   v) Q^(y) is NH—R^(w), NH—CH₂—R_(w), (C₁-C₁₀)alkyl, or        (C₆-C₁₄)aryl, wherein R^(w) is absent or a (C₁-C₁₀)alkyl,        (C₂-C₉)heteroalkyl, (C₆-C₁₄)aryl, or (C₂-C₉)heteroaryl;    -   vii) R^(x) and R^(y) are each independently a pharmaceutically        acceptable end group;    -   ix) X⁻ is independently a halo or any pharmaceutically        acceptable anion,    -   x) Y¹ and Y² are independently H or (C₁-C₁₀)alkyl optionally        substituted by one or more substituents selected from the group        consisting of (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,        (C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, —S—O—(C₁-C₁₀)alkyl,        —O(O)C—(C₁-C₁₀)alkyl, —(C₁-C₁₀)alkyl-COOH,        (C₃-C₁₀)cycloalkyl-COOH, —(O)CH₃, —OH, amide, a dihydroxy group,        represented by Formula (D),

-   -   -   wherein d is an integer from 0 to 25, or

    -   a polyethylene glycol group, represented by Formula (E)

-   -   -   wherein e is an integer from 1 to 400.

In a preferred embodiment of the invention, the amine functionalpolyamides of are compounds of Formula (IV) or Formula (V) where u and vare both 2.

In a preferred embodiment of the invention, the amide functionalpolyamides are a compound comprising the structure of Formula (4).

In one aspect of the invention, the amine functional polyamides are apharmaceutical composition comprising a compound comprising thestructure of Formula (I). In another aspect of the invention, aminefunctional polyamides are a pharmaceutical composition comprising acompound comprising the structure of Formula (II). In yet another aspectof the invention, amine functional polyamides are a pharmaceuticalcomposition comprising a compound comprising the structure of Formula(III). In preferred embodiments of the invention, the amine functionalpolyamides are a pharmaceutical composition comprising a compoundcomprising the structure of Formula (1), Formula (2), or Formula (3). Inyet another preferred embodiment of the invention, the amine functionalpolyamides are a pharmaceutical composition comprising a compoundcomprising the structure of Formula (I), Formula (II), Formula (III),Formula (1), Formula (2) or Formula (3), wherein R_(x) and R_(y) areindependently selected from a methoxy group, a guanidino group, or aguanidinobenzene group.

In another aspect of the invention, amine functional polyamides are apharmaceutical composition comprising a compound comprising thestructure of Formula (IV). In another aspect of the invention, aminefunctional polyamides are a pharmaceutical composition comprising acompound comprising the structure of Formula (V). In a preferredembodiment of the invention, the amine functional polyamides are apharmaceutical composition comprising a compound comprising thestructure of Formula (4).

In another preferred embodiment of the invention, the amine functionalpolyamides are a pharmaceutical composition comprising a compoundcomprising the structure of Formula (I), (II), (III), (IV), (V), (1),(2), (3) or (4) for use in the treatment or prevention of a conditionselected from mucositis, oral mucositis and infection. In yet anotherpreferred embodiment, the amine functional polyamides are apharmaceutical composition comprising a compound comprising thestructure of Formula (I), (II), (III), (IV), (V), (1), (2), (3) or (4)for use in the treatment or prevention of a surgical site infection, alung infection associated with cystic fibrosis, a Pseudomonas aeruginosalung infection, and a Pseudomonas aeruginosa lung infection wherebiofilms are present.

In one embodiment of the invention, the amine functional polyamides arepolymers. In some embodiments, the polymers may comprise a monomercomprising a compound having a repeat unit according to any of Formulas(I), (II), (III), (IV), (V), (1), (2), (3) or (4).

In one embodiment of the invention, the amine functional polyamides arecopolymers. In some embodiments, the copolymers may comprise a monomercomprising a compound having at least one unit according to any ofFormulas (I), (II), (III), (IV), (V), (1), (2), (3) or (4) which iscopolymerized with one or more other comonomers or oligomers or otherpolymerizable groups. Non-limiting examples of suitable comonomers whichmay be used alone or in combination with at least one unit according toany of Formulas (I), (II), (III), (IV), (V), (1), (2), (3) or (4) toform the amine functional polyamides are presented in Table 1.

In one embodiment of the invention, the amine functional polyamides arepolymers or copolymers comprised of about 1 to about 400 repeat unitsaccording to any of Formulas (I), (II), (III), (IV), (V), (1), (2), (3)or (4). In one aspect of the invention, the amine functional polyamidesare polymers or copolymers comprised of about 1 to about 200 repeatunits according to any of Formulas (I), (II), (III), (IV), (V), (1),(2), (3) or (4). In another aspect of the invention, the aminefunctional polyamides are polymers or copolymers comprised of about 1 toabout 100 repeat units according to any of Formulas (I), (II), (III),(IV), (V), (1), (2), (3) or (4). In some embodiments, the aminefunctional polyamides are polymers or copolymers comprised of about 1 toabout 50 repeat units according to any of Formulas (I), (II), (III),(IV), (V), (1), (2), (3) or (4). In an additional embodiment, the aminefunctional polyamides are polymers or copolymers comprised of about 1 toabout 25 repeat units according to any of Formulas (I), (II), (III),(IV), (V), (1), (2), (3) or (4). In yet another embodiment, the aminefunctional polyamides are polymers or copolymers comprised of about 1 toabout 10 repeat units according to any of Formulas (I), (II), (III),(IV), (V), (1), (2), (3) or (4). In other embodiments, the aminefunctional polyamides are polymers or copolymers comprised of about 5 toabout 40 repeat units according to any of Formulas (I), (II), (III),(IV), (V), (1), (2), (3) or (4). In one embodiment, the amine functionalpolyamides are polymers or copolymers comprised of about 5 to about 30repeat units according to any of Formulas (I), (II), (III), (IV), (V),(1), (2), (3) or (4). In another embodiment, the amine functionalpolyamides are polymers or copolymers comprised of about 5 to about 25repeat units according to any of Formulas (I), (II), (III), (IV), (V),(1), (2), (3) or (4). In yet another embodiment, the amine functionalpolyamides are polymers or copolymers comprised of about 5 to about 10repeat units according to any of Formulas (I), (II), (III), (IV), (V),(1), (2), (3) or (4).

In one aspect of the invention, the amine functional polyamides have amolecular weight less than about 10,000 g/mol. In another aspect of theinvention, the amine functional polyamides have a molecular weight lessthan about 9,000 g/mol. In an additional aspect of the invention, theamine functional polyamides have a molecular weight less than about8,000 g/mol. In yet another aspect of the invention, the aminefunctional polyamides have a molecular weight less than about 7,000g/mol.

In one aspect of the invention, the amine functional polyamides areoptionally, independently terminated (R^(x) and R^(y)) with apharmaceutically acceptable end group. Representative examples ofpharmaceutically acceptable end groups will be obvious to one of skillin the art, including H, (C₁-C₁₀)alkyl, (C₂-C₀)heteroalkyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,(C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, —O(O)C—(C₁-C₁₀)alkyl,(C₁-C₁₀)alkyl-COOH, (C₃-C₁₀)cycloalkyl-COOH, —(O)CH₃, —OH, amide, aguanidino group represented by Formula (A)

wherein a is an integer from 0 to 25, a guanidinium chloride grouprepresented by Formula (B),

wherein b is an integer from 0 to 25, a guanidinobenzene grouprepresented by Formula (C),

wherein c is an integer from 0 to 25, a dihydroxy group, represented byFormula (D),

wherein d is an integer from 0 to 25, or a polyethylene glycol group,represented by Formula (E)

wherein e is an integer from 1 to 400

The number of repeat units and the molecular weight of the aminefunctional polyamides are controlled by synthesis of the compound.Methods of preparing preferred amine functional polyamides of theinvention and controlling for the number of repeat units and molecularare described in Example 3.

TABLE 1 Amine Functional Polyamides Polymer Description Structure Poly(4,4′- trimethylene dipiperidine bispropanoic acid--N,N′- dimethyl-1,3-diaminopropane)

Poly (4,4′- trimethylene dipiperidine bispropanoic acid-4,4′-trimethylene dipiperidine)

Poly (4,4′- trimethylene dipiperidine bispropanoic acid-piperazine)

Poly(4,4- trimethylene dipiperidine bispropanoic acid- diaminoethane) Mw<10K

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminopropane)Mw <10K

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminopropane)Mw >10K

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminopropane)Mw 1650

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminopropane)Mw 7.7K

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminopropane)Mw 3K

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminopropane)Mw 5K

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminopropane),Mw 3250

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminopropane),Mw 4700

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminopropane),Mw 2500

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminopropane)

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminopropane)Mw 1400

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminobutane)Mw <10K

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminobutane)Mw >10K

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminotriPEG)Mw <10K

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminotriPEG)Mw >10K

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- N(2-aminoethyl)- diaminoethane)

Poly(4,4′- trimethylenedi- piperidinebisprop- anoic acid-2,2′- diamino-diethylamine) Mw 5.5K

Poly(4,4′- trimethylenedi- piperidinebisprop- anoic acid 2,2′- diamino-diethylamine) Mw ~14,000

Poly(4,4′- trimethylene dipiperidinebis- propanoic acid- 1,4-benzyldiamine) Mw <10K

Poly(4,4′- trimethylene dipiperidinebis- propanoic acid- N(3-aminopropyl)1,3- propane- diamine) Mw <10K

Poly(4,4′- trimethylene dipiperidinebis- propanoic acid- 3,3′-diamino-N-methyl- dipropylamine) Mw <10K

Poly(4,4′- trimethylene dipiperidinebis- propanoic acid- 2,2′-diamino-N-methyl- diethylamine)

Poly(piperazine- bispropanoic acid-1,2-bis(2- aminoethoxy)eth- ane) Mw<10K

Poly(piperazine- bispropanoic acid-2,2- diaminodiethyl- amine) Mw <10K

Poly(piperazine- bispropanoic acid-N-methyl- 2,2- diaminodiethyl- amine)Mw <10K

Poly(piperazine- bispropanoic acid-N(3- aminopropyl)1,3- propane-diamine) Mw <10K

Poly(piperazine- bispropanoic acid-3,3′ diamino-N- methyl-dipropylamine) Mw <10K

Poly(piperazine- bispropanoic acid-1,3- diaminopropane) Mw ~3,700

Poly(piperazine- bispropanoic acid-1,4- diaminobutane) Mw ~4,400

Poly(4,4′- dipiperidinebis- propanoic acid- 2,2′-diamino- diethylamine)Mw <5K

Poly(4,4′- dipiperidinebis- propanoic acid- 2,2′-diamino- diethylamine)Mw 5.1K

Poly(4,4′- dipiperidinebis- propanoic acid- 2,2′-diamino N- methyldiethylamine) Mw <5K

Poly(4,4′- dipiperidinebis- propanoic acid- 2,2′-diamino N- methyldiethylamine) Mw <5K

Poly(4,4′- dipiperidinebis- propanoic acid- 3,3′-diamino- dipropylamine)Mw <5K

Poly(4,4′- dipiperidinebis- propanoic acid- 3,3′-diamino- dipropylamine)Mw <5K

Poly(4,4′- dipiperidinebis- propanoic acid- 3,3′-diamino-N- methyl-dipropylamine) Mw <5 k

Poly(4,4′- dipiperidinebis- propanoic acid- 3,3′-diamino-N- methyl-dipropylamine) Mw ~5.5K

Poly(4,4′- dipiperidinebis- propionic acid- ethylenediamine) Mw <5K

Poly(4,4′- dipiperidinebis- propionic acid-1,3- diaminopropane) Mw <5K

Poly(4,4′- dipiperidinebis- propionic acid-1,4- diaminobutane) Mw <5K

Poly(4,4′- trimethylenedi- piperidinebisprop- ionic acid-bis(4-aminobutyl)ether) Mw <5K

Poly(4,4′- trimethylenedi- piperidinebisprop- ionic acid-2- dydroxy 1,3-diaminopropane) Mw <5K

Poly(4,4′- trimethylenedi- piperidine-1,3- diamninopropane- N,N′-di-3-propionic acid) Mw <5K

Poly (4,4′ trimethylene dipiperidine bispropanoic acid--N,N′-dimethyl-1,3- diaminopropane), Mw 1K

Poly(4,4- trimethylene dipiperidinebis- propanoic acid 4,4′-dipiperidine), Mw 10631

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- histamine), Mw2.3K

40 mol % glycidol modified poly(4,4- trimethylene dipiperidinebis-propanoic acid- diaminopropane), Mw 8000

40 mol % glycidol modified poly(4,4- trimethylene dipiperidinebis-propanoic acid- diaminopropane), Mw 4700

40 mol % glycidol modified Poly(4,4- trimethylene dipiperidinebis-propanoic acid- diaminopropane) Mw 5000

40 mol % glycidol modified Poly(4,4- trimethylene dipiperidinebis-propanoic acid- diaminopropane) Mw 5000

100 mol % glycidol modified Poly(4,4- trimethylene dipiperidinebis-propanoic acid- diaminopropane), Mw 8K

25 mol % glycidol modified Poly(4,4- trimethylene dipiperidinebis-propanoic acid- diaminopropane), Mw 7800

50 mol % glycidol modified Poly(4,4- trimethylene dipiperidinebis-propanoic acid- diaminopropane), Mw 7800

150 mol % glycidol modified Poly(4,4- trimethylene dipiperidinebis-propanoic acid- diaminopropane), Mw 7800

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminopropane)modified with 200 mol % of glycidol, Mw 7800

Poly (4,4′- trimethylene dipiperidine bispropanoic acid--3-(dimethylamino) 1-propylamine), Mw 1K

Poly(2,2- bipyrrrolidine bispropanoic acid- diaminopropane), Mw 2.5K

Poly(2,2′- bipyrrolidine bispropanoic acid-butyl- diamine)

Poly(2,2′- bipyrrolidine bispropanoic acid-penta- diamine)

Poly(2,2′- bipyrrolidine bispropanoic acid-ethyl- diamine)

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- aminomethyl-benzene)

Poly[4,4- trimethylene dipiperidinebis- propanoic acid-(1-aminomethyl-4- guanidinemethyl- benzene)]

Carboxy terminated Poly(4,4- trimethylene dipiperidinebis- propanoicacid- diaminopropane)

Methyl ester terminated Poly(4,4- trimethylene dipiperidinebis-propanoic acid- diaminopropane)

Guanidine terminated Poly(4,4- trimethylene dipiperidinebis- propanoicacid- diaminopropane)

Guanidine terminated Poly(4,4- trimethylene dipiperidinebis- propanoicacid- diaminopropane) Mw 4700

Guanidine terminated poly(4,4- trimethylene dipiperidinebis- propanoicacid- diaminopropane) Mw 7700

Poly(4,4- trimethylene dipiperidinebis- propanoic acid- diaminopropane)(guanidine ended)

4,4-trimethylene dipiperidinebis- propanoic acid- diaminopropane

4- guanidinobenzene terminated Poly(4,4- trimethylene dipiperidinebis-propanoic acid- diaminopropane)

Poly(4,4′- trimethylenedi- piperidine bisethylacrylamide- co-1,3-diamine propane)

Poly(4,4′- trimethylenedi- piperidine bisethylacrylamide- co-1-amino-3-guanidine propane)

4,4-trimethylene dipiperidinebis- propanoic acid-1- amino-3- guanidinepropane

Poly(4,4′- trimethylenedi- piperidine bisethylacrylamide- 1,3-diaminepropane)-co- Poly(4,4′- trimethylenedi- piperidine bisethylacrylamide-1- aminobutyl-3- carbamoyl- pyridinium)

Poly(4,4′- trimethylenedi- piperidine bisethylacrylamine- 1-aminobutyl-3- carbamoyl- pyridinium)

4,4′-trimethylene dipiperidinebis- propanoic acid- diaminopropanepentamer

4,4′-trimethylene dipiperidinebis- propanoic acid- diaminopropaneheptamer

Poly(4,4′- trimethylene dipiperidinebis- propanoic acid-N- glycidoldipropylene triamine)

Poly(4,4′- trimethylene dipiperidinebis- propanoic acid-N- glycidoldiethylene triamine)

Poly(4,4′- trimethylene dipiperidinebis- propanoic acid-N- glycidoldiethylene triamine)

In an embodiment of the invention, the amine functional polyamides areadministered as a pharmaceutical composition. In another embodiment ofthe invention, the amine functional polyamides are administered in aneffective amount to achieve the desired therapeutic effect. The skilledartisan will be able to determine the effective amount of the aminefunctional polyamides depending on the individual and the conditionbeing treated.

In one embodiment of the invention, the amine functional polyamides areused in the treatment all forms of mucositis, and are particularlyeffective when used to treat oral mucositis. Treatment includesprophylactic and therapeutic uses of the disclosed amine functionalpolyamides and uses of the disclosed pharmaceutical compositionscomprising amine functional polyamides. Desired prophylactic effectsinclude prevention and inhibition of mucositis, reduction in severity ofmucositis, reduction in size of mucositis lesions and reduction inlikelihood of developing mucositis through the application oradministration of amine functional polyamides or pharmaceuticalcompositions comprising amine functional polyamides. Desired therapeuticeffects include amelioration of the discomfort associated with themucositis, and/or increased rate of healing of mucositis lesion.

In one embodiment, the amine functional polyamides and pharmaceuticalcompositions comprising amine functional polyamides can be used to treatall forms of infection, including but not limited to SSI, lung infectionin CF patients, and C. aeruginosa lung infection in CF patients with orwithout biofilm formation. The amine functional polyamides andpharmaceutical compositions comprising amine functional polyamides canbe used in prophylactic and therapeutic applications to treat andprevent infection.

In another embodiment, the amine functional polyamides andpharmaceutical compositions comprising amine functional polyamides canbe used to treat all forms of SSIs. Treatment includes prophylactic andtherapeutic uses of the disclosed amine functional polyamides and usesof the disclosed pharmaceutical compositions comprising amine functionalpolyamides. A desired prophylactic use is the immediate administrationof amine functional polyamides or pharmaceutical compositions comprisingamine functional polyamides to the surgical wound post-surgery in orderto prevent and/or reduce the likelihood of developing a SSI. Anotherdesired prophylactic use is the administration of amine functionalpolyamides or pharmaceutical compositions comprising amine functionalpolyamides prior to surgery in order to prevent and/or reduce thelikelihood of developing a SSI. Desired therapeutic effects include thetreatment of an existing SSI through the application or administrationof amine functional polyamides or pharmaceutical compositions comprisingan amine functional polyamide.

In another embodiment, the amine functional polyamides andpharmaceutical compositions comprising amine functional polyamides canbe used to treat all forms of lung infections and chronic lunginfections associated with CF, including C. aeruginosa lung infectionsin CF patients with or without biofilm formation. Treatment includesprophylactic and therapeutic uses of the disclosed amine functionalpolyamides and uses of the disclosed pharmaceutical compositionscomprising amine functional polyamides. Desired therapeutic effectsinclude the treatment of an existing lung infection or chronic lunginfection through the administration of amine functional polyamides orpharmaceutical compositions comprising an amine functional polyamide. Inone embodiment, the amine functional polyamides and pharmaceuticalcompositions comprising amine functional polyamides are used to treat P.aeruginosa infections associated with CF without biofilm formation. Inanother embodiment, the amine functional polyamides and pharmaceuticalcompositions comprising amine functional polyamides are used to treat P.aeruginosa infections associated with CF with biofilm formation. Adesired prophylactic use is the administration of amine functionalpolyamides or pharmaceutical compositions comprising amine functionalpolyamides to the CF patient in order to prevent and/or reduce thelikelihood of developing a lung infection, including C. aeruginosa lunginfections. Desired therapeutic effects include the treatment of anexisting lung infection or chronic lung infection through theadministration of amine functional polyamides or pharmaceuticalcompositions comprising an amine functional polyamide.

The amine functional polyamides of the present invention may beadministered alone or in a pharmaceutical composition comprising aminefunctional polyamides. Suitable pharmaceutical compositions may comprisean amine functional polyamide and one or more pharmaceuticallyacceptable excipients. The form in which the polymers are administered,for example, powder, tablet, capsule, solution, or emulsion, depends inpart on the route by which it is administered. The amine functionalpolyamides can be administered, for example, topically, orally,intranasally, by aerosol or rectally. Suitable excipients include, butare not limited to, are inorganic or organic materials such as gelatin,albumin, lactose, starch, stabilizers, melting agents, emulsifyingagents, salts and buffers. Suitable pharmaceutically acceptableexcipients for topical formulations such as ointments, creams and gelsinclude, but are not limited to, commercially available inert gels orliquids supplemented with albumin, methyl cellulose, or a collagenmatrix.

The amine functional polyamides and pharmaceutical compositionscomprising amine functional polyamides can be administered alone or incombination with one or more additional drugs. Additional drugsadministered in combination with the amine functional polyamides andpharmaceutical compositions comprising amine functional polyamides ofthe present invention include antibiotics and other compounds, includingthose used prophylactically and/or therapeutically for the treatment orprevention of mucositis and infection, including SSI and lung infectionand chronic lung infection associated with CF, especially P. aeruginosainfection, with or without biofilm formation. The additional drugs maybe administered concomitantly with the amine functional polyamide orpharmaceutical compositions comprising amine functional polyamides. Theadditional drugs may also be administered in series with the aminefunctional polyamide or pharmaceutical compositions comprising aminefunctional polyamides. The pharmaceutical composition comprising aminefunctional polyamides may also further comprise a drug usedprophylactically and/or therapeutically for the treatment or preventionof mucositis and infection, including SSI and lung infection and chroniclung infection associated with CF, especially P. aeruginosa infection,with or without biofilm formation.

EXAMPLES Example 1 In vitro Studies Example 1-1 Cytotoxicity Assay,RPTEC Cells and NHDF Cells

Mammalian cell cytotoxicity assays were performed using two primaryhuman cell lines: renal proximal tubule epithelial cells (RPTEC—CambrexCC-2553) and normal human dermal fibroblasts (NHDF—Cambrex CC-2509).Cells were plated at 3,000 cells/well (RPTEC) or 5,000 cells/well (NHDF)in 96-well plates and incubated overnight at 37° C. The compounds wereadded to the wells, and the cells were incubated for 4 days. Alomar Bluewas added to one set of plates and incubated for 4 hours. The plateswere read when the compound was added (time zero) and at the end of thestudy. Fluorescence was read using 530 nm (excitation) and 590 nm(emission) according to the manufacturer's instructions. The 50%inhibitory concentration (IC₅₀) was calculated as 50% of the maximumsignal minus the value at time zero. The 50% lethal concentration (LC₅₀)was calculated as 50% of the time zero value minus the minimum signal.

Table 2 displays the renal proximal tubule epithelial cells and normalhuman dermal fibroblasts IC₅₀ and LC₅₀ for selected compounds.

Example 1-2 Cytotoxicity Assay, Human Lung Epithelial Cells

Cytoxicity of the polymers towards human lung epithelial cells wasperformed using human lung epithelial Carcinoma cell line (A 549—ATCC #CCL-185). The cells were incubated for 96 hours at 7° C. with 5% CO₂ ina 96-well plate. CellTiter-Glo® (Promega) reagent was added to theplates. The plates were read by measuring the luminescence arising fromluciferase catalyzed reaction of luciferin with ATP according to themanufacturer's suggested protocol. The concentration of ATP is directlyproportional to cell viability; accordingly, higher luminescencemeasures high cell viability.

Table 2 displays the human lung epithelial cells IC₅₀ for selectedcompounds.

Example 1-3 Erythrocyte Lysis Assay

The compounds were incubated overnight at 37° C. in Dulbecco'sphosphate-buffered saline containing fresh washed erythrocytes at ahematocrit of 1%. After incubation, the plates were centrifuged and thesupernatant transferred to flat-bottomed 96-well plates. The supernatantwas assayed using the QuantiChrom Hemoglobin kit according to themanufacturer's instructions. The IC₅₀ values were calculated usingGraphPad Prism.

Table 2 displays the IC₅₀ values for selected compounds.

Example 1-4 Minimum Inhibitory Concentration Assay

The minimum inhibitory concentration (MIC) assay determines the lowestconcentration of an antimicrobial agent required to inhibit the growthof test organisms after incubation. MIC assays were performed against aninternal standard panel of organisms to identify compounds withantimicrobial activity. The MIC assay was subsequently repeated againstother specialized microbial panels. Assays were conducted against thefollowing clinically relevant microorganisms: Staphylococcus aureussubsp. aureus, Staphylococcus epidermis, Escherichia coli, Pseudomonasaeruginosa, Haemophilius influenzae. The compounds were tested forbacteriocidal activity, time course of killing, toxicity against tissueculture cells grown in vitro, and in some cases were tested forantimicrobial activity in vivo.

The MIC assays were performed according to the Performance Standards forAntimicrobial Susceptibility Testing, 2006, vol. M100-S15, FifteenthInformational Supplement, NCCLS, 940 West Valley Road, Suite 1400,Wayne, Pa. 19087.

The polymers tested were dissolved in 0.85% saline to a finalconcentration of either 830 or 1000 μg/mL and the pH was adjusted to7.0. The solution was then filter-sterilized through a 0.22 μm filter.Two-fold serial dilutions of polymer were prepared in Mueller-Hintonbroth with cations aliquotted into 96-well microtiter plates. The plateswere then inoculated with 5×10⁵ cells/mL of target organism andincubated 18-24 hours at 35° C. The optical density (OD) was read at 590nm, and microorganism growth was scored (OD>0.1 is considered to begrowth; OD<0.1 is considered to be growth inhibition). The MIC value isthe lowest concentration of compound that inhibits growth; accordingly,a higher MIC value indicates less potency where a lower MIC valuedindicated more potency.

MIC values of representative amine functional polyamides againstclinically relevant microorganisms are presented in Table 2.

TABLE 2 In vitro Results of Representative Amine Functional PolyamidesCytotoxicity Assay [Kidney Epithelial and Human Dermal Fibroblast IC₅₀and LC₅₀], Erythrocyte Lysis Assay [Hemolysis IC₅₀], and MIC valuesagainst Clinically Relevant Microorganisms Staphy- CytotoxicityCytotoxicity lococcus Pseudo- Haemo- Cytotoxicity Cytotoxicity (Human(Human Erythrocyte aureus Staphy- Escher- monas philus (Kidney (KidneyDermal Dermal Lung Lysis subsp. lococcus ichia aeru- influ- PolymerEpithelial Epithelial Fibroblast Fibroblast Epi (Hemolysis aureusepidermis coli ginosa enzae Description IC₅₀) LC₅₀) IC₅₀) LC₅₀) IC₅₀IC₅₀) (MIC) (MIC) (MIC) (MIC) (MIC) Poly(4,4- 32.2 55.7 141.3 189.3391 >6400 1.0 0.3 2.0 32 16.0 trimethylene dipiperidine- bispropanoicacid- diamino- propane) <10K Poly(4,4- 5.3 8.7 16.3 22.1 74.1 >6400 4.01.0 4.0 32.0 16.0 trimethylene dipiperidine- bispropanoic acid- diamino-butane) >10K Poly(4,4- 28.6 61.9 138.3 196.2 377.9 >6400 4.0 1.0 4.0128.0 16.0 trimethylene dipiperidine- bispropanoic acid- diamino-butane) <10K Poly(4,4- 33 78 178 273 799 >6400 32.0 4.0 16.0 128.0 128.0trimethylene dipiperidine- bispropanoic acid- diaminoethane) <10KPoly(4,4- 45.6 133.3 218.4 436.5 427.1 2066 128.0 128.0 32.0 128.0 128.0trimethylene dipiperidine- bispropanoic acid- diaminotri- PEG) <10KPoly(4,4- 2.7 6.9 8.5 18.8 29.0 1792 128.0 8.0 8.0 64.0 128.0trimethylene dipiperidine- bispropanoic acid- diaminotri- PEG) >10KPoly(4,4- 32.2 55.7 141.3 189.3 — >6400 1.0 0.5 4.0 64.0 16.0trimethylene dipiperidine- bispropanoic acid- diamino- propane) <10KPoly(4,4- <1.463 <1.463 1.7 2.0 6.5 9 4.0 0.5 8.0 16.0 64.0 trimethylenedipiperidine- bispropanoic acid-N(2- aminoethyl)- diaminoethane)Poly(4,4′- <1.463 <1.463 <1.463 <1.463 13.9 2220.0 1.0 0.5 8.0 64.0 32.0trimethylene dipiperidine- bispropanoic acid-N(3- aminopropyl)1,3-propane diamine) <10K Poly(4,4- 10.8 25.6 62.6 99.7 333.0 >6400 1.00.5 4.0 16.0 16.0 trimethylene dipiperidine- bispropanoic acid-diamino-propane) <10K Poly(4,4′- <1.463 <1.463 <1.463 1.9 65.0 >6400 8.0 1.016.0 64.0 64.0 trimethylene dipiperidine- bispropanoic acid-3,3′-diamino-N- methyl- dipropylamine) <10K Poly(4,4′- 2.9 7.2 9.3 20.1125.5 >6400 4.0 1.0 8.0 64.0 64.0 trimethylene dipiperidine-bispropanoic acid-2,2′- diamino-N- methyl- diethylamine) Poly(4,4′- 2.02.9 4.703 5.1 31.3 87.0 32.0 8.0 16.0 128.0 128.0 trimethylenedipiperidine- bispropanoic acid-1,4- benzyldiamine) <10KPoly(piperazine- >3200 >3200 >3200 >3200 >6400 >6400 128.0 128.0 128.0128.0 128.0 bispropanoic acid-1,2- bis(2- aminoethoxy) ethane) <10KPoly(piperazine- 212.1 838.5 1111.6 1999.8 >6400 >6400 128.0 64.0 128.0128.0 128.0 bispropanoic acid-2,2- diaminodiethyl- amine) <10KPoly(piperazine- 5.3 33.7 94.7 246.2 4164.4 >6400 128.0 32.0 128.0 128.0128.0 bispropanoic acid-3,3′- diamino-N- methyl- dipropylamine) <10KPoly(piperazine- <1.463 3.0 15.3 35.0 497.0 >6400 8.0 4.0 128.0 128.0128.0 bispropanoic acid-N(3- aminopropyl) 1,3-propane diamine) <10KPoly(piperazine- 1204.2 >3200 3068.6 >3200 >6400 >6400 128.0 128.0 128.0128.0 128.0 bispropanoic acid-N- methyl-2,2- diaminodiethyl- amine) <10KPoly(4,4′- <1.463 1.5 2.0 3.4 14.6 88.0 4.0 0.3 4.0 16.0 64.0trimethylene- dipiperidinebis- propanoic acid- 2,2′-diamino-diethylamine) 5.5K Poly(4,4′- <1.5 2 2 4 50.0 1284.0 1.0 0.5 16.0 64.0128.0 dipiperidine- bispropanoic acid-2,2′- diamino- diethylamine) 5.1KPoly(4,4′- <1.5 2 4 7 93.0 >6400 2.0 0.5 32.0 64.0 128.0 dipiperidine-bispropanoic acid-2,2′- diamino N- methyl diethylamine) <5K Poly(4,4′- 59 20 30 294.0 >6400 8.0 0.5 32.0 32.0 128.0 dipiperidine- bispropanoicacid-2,2′- diamino N- methyl diethylamine) <5K Poly(4,4′- 11 21 61 88823.0 >6400 8.0 1.0 64.0 64.0 128.0 dipiperidine- bispropanoicacid-2,2′- diamino N- methyl diethylamine) ~5K Poly(4,4′- <1.5 <1.5 <1.5<1.5 10.0 300.0 1.0 0.3 16.0 32.0 128.0 dipiperidine- bispropanoicacid-3,3′- diamino- dipropylamine) <5K Poly(4,4′- <1.5 <1.5 2 330.0 >6400 1.0 0.5 16.0 64.0 128.0 dipiperidine- bispropanoic acid-3,3′-diamino- dipropylamine) ~5K Poly(4,4′- <1.5 2 3 5 81.0 >6400 8.0 1.032.0 64.0 128.0 dipiperidine- bispropanoic acid-3,3′- diamino-N- methyl-dipropylamine) ~5K Poly(4,4′- <1.5 <1.5 2 3 26.0 3622.0 2.0 0.5 16.032.0 128.0 dipiperidine- bispropanoic acid-3,3′- diamino-N- methyl-dipropylamine) >5K Poly(4,4′- <1.463 <1.463 2.1 2.8 6.8 9.0 4.0 1.0 8.016.0 128.0 trimethylene- dipiperidinebis- propanoic acid- 2,2′-diaminodiethylamine) ~14,000 Poly(piperazine- 924 >3200 >3200 >3200 >6400 >6400128.0 128.0 128.0 128.0 128.0 bispropanoic acid-1,3- diamino- propane)~3,700 Poly(piperazine- 541 1946 1905 3080 4539.0 3388.0 128.0 64.0128.0 128.0 128.0 bispropanoic acid-1,4- diaminobutane) ~4,400Poly(4,4′- 6 11 7 16 22.0 >6400 1.0 0.1 16.0 1.0 32.0 dipiperidine-bispropionic acid-1,3- diaminopropane) <5K Poly(4,4′- 4 7 5 1722.0 >6400 2.0 0.3 8.0 8.0 32.0 dipiperidine- bispropionic acid-1,4-diaminobutane) <5K Poly(4,4′- 8 21 19 29 77.0 >6400 4.0 0.5 16.0 32.0128.0 dipiperidine- bispropionic acid- ethylenediamine) <5K Poly(4,4′- 23 2 3 4.0 6.3 16.0 4.0 8.0 16.0 128.0 trimethylene- dipiperidine-1,3-diamnino- propane- N,N′-di-3- propionic acid) <5K Poly(4,4′- 15 8050 127 63.0 >6400 4.0 1.0 8.0 128.0 32.0 trimethylene- dipiperidinebis-propionic acid 2-dydroxy 1,3-diamino- propane) <5K Poly(4,4′- 2 5 3 58.0 165.0 128.0 8.0 8.0 128.0 16.0 trimethylene- dipiperidinebis-propionic acid- bis(4-amino- butyl)ether) <5K Poly (4,4′ - <1.463 3 3 42 5.6 16.0 4.0 16.0 32.0 128.0 trimethylene dipiperidine bispropanoicacid-4,4′- trimethylene dipiperidine) Poly (4,4′ - <1.463 2 5 11 6 11.3128.0 4.0 4.0 16.0 128.0 trimethylene dipiperidine bispropanoicacid--N,N′- dimethyl-1,3- diamino- propane) Poly (4,4′- 12 22 53 75 2159.0 128.0 128.0 128.0 128.0 128.0 trimethylene dipiperidinebispropanoic acid- piperazine) Poly(4,4- 2 3 5 8 6.0 636.0 0.5 0.3 2.04.0 8.0 trimethylene dipiperidine- bispropanoic acid-diamino- propane)modified with 40 mol % of glycidol, 8K Poly(4,4- 3.1 5.5 9.4 15.521.5 >3200 0.5 0.1 2.0 4.0 8.0 trimethylene dipiperidine- bispropanoicacid-diamino- propane), 1650 Poly(4,4- 1.6 2.9 6.8 9.9 10.8 651.0 1.00.3 2.0 8.0 8.0 trimethylene dipiperidine- bispropanoic acid-diamino-propane), 5K Poly(4,4- <1.5 <1.463 2.0 2.8 3.7 50.0 2.0 0.3 2.0 4.0 8.0trimethylene dipiperidine- bispropanoic acid-diamino- propane), 7.7KPoly(4,4- 8.7 12.3 20.7 32.8 17 1260.0 1.0 0.3 4.0 16.0 4.0 trimethylenedipiperidine- bispropanoic acid-diamino- propane), 3K Poly(4,4- 3.0 5.07.0 11.0 7.0 500.0 8.0 0.5 8.0 16.0 16.0 trimethylene dipiperidine-bispropanoic acid-diamino- propane) modified with 100 mol % of glycidol,8K Poly(4,4- <1.5 2.0 2.0 4 <1.5 3.2 16.0 4.0 8.0 16.0 128.0trimethylene dipiperidine- bispropanoic acid-4,4′- dipiperidine), 10,631Poly(4,4- 7.0 16.0 18.0 27.0 9.0 19.0 128.0 32.0 32.0 128.0 128.0trimethylene dipiperidine- bispropanoic acid- histamine), 2.3K Poly(4,4-5.8 10.3 — — — >3200 0.5 0.1 2.0 8.0 8.0 trimethylene dipiperidine-bispropanoic acid-diamino- propane), 3250 Poly(4,4- 1.9 3.3 — — —176.497 1.0 0.3 1.0 4.0 8.0 trimethylene dipiperidine- bispropanoicacid-diamino- propane), 4700 Poly(4,4- 2 3 — — — 96.0 2.0 0.5 4.0 8.016.0 trimethylene dipiperidine- bispropanoic acid-diamino- propane)modified with 200 mol % of glycidol, 7800 Poly(4,4- 2 4 — — — 152.0 2.01.0 8.0 16.0 16.0 trimethylene dipiperidine- bispropanoic acid-diamino-propane) modified with 150 mol % of glycidol, 7800 Poly(4,4- 2 4 — — —110.0 4.0 0.5 8.0 16.0 16.0 trimethylene dipiperidine- bispropanoicacid-diamino propane) modified with 50 mol % of glycidol, 7800 Poly(4,4-8.7 51.2 — — — >3200 0.5 0.3 8.0 64.0 32.0 trimethylene dipiperidine-bispropanoic acid-diamino- propane), 2500 Poly(4,4- 2 2 — — — 55.0 2.00.5 4.0 8.0 16.0 trimethylene dipiperidine- bispropanoic acid-diamino-propane) modified with 25 mol % of glycidol, 7800 Poly (4,4′- 32 70 — —— 182.0 128.0 32.0 128.0 128.0 128.0 trimethylene dipiperidine-bispropanoic acid--3- (dimethyl- amino) 1-propyl- amine), 1K Poly (4,4′-4 7 — — — 76.0 128.0 8.0 16.0 32.0 128.0 trimethylene dipiperidinebispropanoic acid-N,N′- dimethyl-1,3- diamino- propane), 1K Poly(2,2- 28164 — — — >3200 128.0 16.0 128.0 128.0 128.0 bipyrrolidine bispropanoicacid-diamino- propane), 2.5K Poly(2,2′- 12 314 — — — >3200 128.0 128.0128.0 128.0 128.0 bipyrrolidine bispropanoic acid-butyl diamine)Poly(2,2′- 73 292 — — — >3200 128.0 128.0 128.0 128.0 128.0bipyrrolidine bispropanoic acid-ethyl diamine) Poly(2,2′- 21 297 — —— >3200 128.0 128.0 128.0 128.0 128.0 bipyrrolidine bispropanoicacid-penta diamine) 4,4′- >512 >512 — — 259.0 >3200 16.0 1.0 16.0 >12864.0 trimethylene dipiperidine- bispropanoic acid-diamino- propanepentamer 4,4′- 190 >512 — — 418.0 >3200 2.0 1.0 8.0 >128 128.0trimethylene dipiperidine- bispropanoic acid-diamino- propane heptamerPoly(4,4- 2 4 — — 10 738.0 2.0 0.3 2.0 8.0 8.0 trimethylenedipiperidine- bispropanoic acid-diamino- propane) (guanidine ended) 40mol % 3 5 — — 7 757.0 0.5 0.1 1.0 8.0 4.0 modified Poly(4,4-trimethylene dipiperidine bispropanoic acid-diamino- propane) 40 mol % 26 — — 8 118.0 1.0 0.3 2.0 8.0 4.0 modified Poly(4,4- trimethylenedipiperidine- bispropanoic acid-diamino- propane) Poly(4,4′- >512 >512 —— >512 >3200 >128 >128 >128 >128 >128 trimethylene dipiperidine-bispropanoic acid-N- glycidol diethylene triamine) Poly(4,4′- 72 178 —— >512 >3200 >128 >128 >128 >128 >128 trimethylene dipiperidine-bispropanoic acid-N- glycidol diethylene triamine) Poly(4,4′- 70 161 —— >512 >3200 >128 32.0 >128 >128 >128 trimethylene dipiperidine-bispropanoic acid-N- glycidol dipropylene triamine) Poly(4,4′- 20 32 — —— 267.0 >128 8.0 64.0 128.0 >128 trimethylene- dipiperidinebisethylacryl- amide-co-1,3- diamine propane) Poly(4,4′- 22 34 — — —122.0 16.0 8.0 16.0 64.0 >128 trimethylene- dipiperidine bisethylacryl-amide-co-1- amino-3- guanidine propane) 4,4- >512 >512 — —— >3200 >128 >128 >128 >128 >128 trimethylene dipiperidine- bispropanoicacid-1-amino- 3-guanidine propane Poly(4,4- 82 499 — — — >3200 4.0 4.016.0 >128 128.0 trimethylene dipiperidine- bispropanoic acid-diaminopropane), 1400 Poly(4,4′- 5 10 — — — 44.0 32.0 2.0 8.0 16.0 >128trimethylene- dipiperidine bisethylacryl- amide-1,3- diaminepropane)-co- Poly(4,4′- trimethylene- dipiperidine bisethylacryl-amide-1- aminobutyl-3- carbamoyl- pyridinium) Poly(4,4′- 11 16 — — —83.0 >128 32.0 64.0 >128 >128 trimethylene- dipiperidine bisethylacryl-amine-1- aminobuty1-3- carbamoyl- pyridinium) 40 mol % 1 2 — — — 287.01.0 0.5 2.0 4.0 8.0 glycidol modified poly(4,4- trimethylenedipiperidine- bispropanoic acid-diamino- propane), 4700 Guanidine 1 4 —— — 334.0 1.0 0.5 2.0 4.0 8.0 terminated Poly(4,4- trimethylenedipiperidine- bispropanoic acid-diamino- propane), 4700 Guanidine 1 1 —— — 18.0 1.0 0.5 2.0 4.0 8.0 terminated poly(4,4- trimethylenedipiperidine- bispropanoic acid-diamino- propane), 7700 Carboxy 43 >512— — — >3200 64.0 32.0 128.0 >128 >128 terminated Poly(4,4- trimethylenedipiperidine- bispropanoic acid-diamino- propane) Methyl ester 1.5 4 — —— 152.0 4.0 0.5 4.0 16.0 8.0 terminated Poly(4,4- trimethylenedipiperidine- bispropanoic acid-diamino- propane) Guanidine 93 169 — —— >3200 1.0 0.3 2.0 64.0 16.0 terminated Poly(4,4- trimethylenedipiperidine- bispropanoic acid-diamino- propane), 2200 Poly(4,4- 4 10 —— — 14.0 64.0 8.0 16.0 16.0 >128 trimethylene dipiperidine- bispropanoicacid- aminomethyl benzene) 4,4 >512 >512 — —— >3200 >128 >128 >128 >128 >128 trimethylene dipiperidine- bispropanoicacid-diamino- propane Poly[4,4- 3 5 — — — 52.0 4.0 64.0 8.0 64.0 >128trimethylene dipiperidine- bispropanoic acid-(1-amino methyl-4-guanidine- methyl benzene)] 4- 6 12 — — — 1142 4.0 2.0 4.0 64.0 32.0guanidino- benzene terminated Poly(4,4- trimethylene dipiperidine-bispropanoic acid-diamino- propane) Poly(4,4- 29.6 110.1 — — — >3200 1.00.5 4.0 64.0 16.0 trimethylene dipiperidine- bispropanoic acid-diamino-propane), <10K —indicates not tested.

Example 1-5 Inhibition of Pseudomonas aeruginosa in Cystic FibrosisBronchial Epithelial Cells

Cystic fibrosis bronchial epithelial (CFBE) cells were grown in 12-wellplates for 7-9 days. The cells were washed twice with imaging mediumbefore Pseudomonas aeruginosa (mucoid strain, SMC 1585) was inoculatedinto each well at a multiplicity of infection (MOI) of ˜30 (˜6×10⁶cfu/well). The plates were incubated at 37° C., 5% CO₂ for 1 hour toallow bacterial attachment to the airway cells. The supernatant was thenreplaced with imaging medium containing 0.4% arginine and then incubatedfor 5 hours to form biofilms on CFBE cells. To estimate the efficacy ofantimicrobial polymer treatment in preformed biofilms, the plates werewashed twice with imaging medium and antimicrobial agent (antimicrobialpolymer or tobramycin [positive control]) were applied at designatedconcentrations to disrupt established biofilms for 16 hours. Thesupernatant was then removed and washed twice with imaging medium. CFBEcells were lysed with 0.1% Triton X-100 for approximately 15 minutes.The lysate was vortexed for 3 minutes before serial dilution and spottitration onto LB plates to determine the cfu/well. The bacterial strainwas defined as ‘susceptible’ to the antibiotic treatment in the staticco-culture model if the CFBE monolayers were not disrupted afterovernight antibiotic treatment and there was more than a 2 log₁₀difference in cfu recovery between no treatment and antibioticantimicrobial agent treatment.

To test the ability of antibiotics to prevent biofilm formation, thesecompounds were applied after the 1 hour period for bacterial attachment.The plates were incubated for 5 hours, and cfu/well was determined asdescribed above. The detection limit of the static co-culture assay was200 cfu/well. All experiments were performed at least three times. Thesusceptibility of Pseudomonas aeruginosa biofilm toPoly(4,4-trimethylene dipiperidinebispropanoic acid-diaminopropane)<10Kis displayed in Figure I below.

Example 2 In vivo Studies Example 2-1 Toxicity—Maximum Tolerated Dose

Acute, 24 hour, toxicity studies to determine the maximum tolerated doseof a compound were carried out in male rats and mice of approximately8-10 weeks of age. Animals were housed singly in standard polycarbonatecages and fed normal chow diets. Following one week of acclimation,compounds were administered in a single intraperitoneal (I.P.) orintravenous (I.V.) dose, typically in a PBS vehicle. The doses generallyranged from 1 mg/kg to as high as 400 mg/kg. Animals were observed forsigns of pain, distress, and local or systemic signs of toxicity for onehour post-dosing, and then in 1 hour intervals for 6 hours after dosing.The following day at 24 hours post-dose, the animals were sacrificed andblood removed for serum chemistry analysis. Serum chemistry analysesperformed include: ALT, AST, Creatinine and Urea Nitrogen. Major organswere also examined for abnormal signs.

Table 3 displays the Maximum Tolerated Dose (MTD) for select testcompounds at select routes of administration.

TABLE 3 Maximum Tolerated Dose (MTD) Animal Route of Treatment ModelAdministration MTD Poly (4,4′-trimethylene dipiperidine Rat I.P.  5mg/kg bispropanoic acid-co-1,3-diamino propane), MW = 4,700 Poly(4,4′-trimethylene dipiperidine Rat I.P.  5 mg/kg bispropanoicacid-co-1,3-diamino propane), MW = 2,500 Poly(4,4-trimethylene Mice I.P. 5 mg/kg dipiperidinebispropanoic acid- diaminopropane), MW < 10K Poly(4,4′-trimethylene dipiperidine Mice I.V. 40 mg/kg bispropanoicacid-co-1,3-diamino propane), MW = 2,500

Example 2-2 Efficacy—Surgical Site Infection

The test compound, poly(4,4-trimethylene dipiperidinebispropanoicacid-diaminopropane) modified with 40 mol % of glycidol, was evaluatedfor anti-infective activity against Staphylococcus aureus, MethicillinResistant (MRSA) and Escherichia coli (E. coli) in mice. Male ICR miceweighing approximately 22 g were used to evaluate the anti-infectiveactivity against each bacterium.

Example 2-2(a) MRSA

Five groups of 10 male mice were inoculated intraperitoneally with aLD₉₀₋₁₀₀ of MRSA (1.90×10⁸ CFU/mouse) suspended in 0.5 mL of brain heartinfusion (BHI) broth containing 5% mucin. One hour after bacteriainoculation, groups of 10 animals were intraperitoneally administeredone of the following:

-   -   0.2 mg/kg poly(4,4-trimethylene dipiperidinebispropanoic        acid-diaminopropane) modified with 40 mol % of glycidol        suspended in 0.9% NaCl,    -   5 mg/kg poly(4,4-trimethylene dipiperidinebispropanoic        acid-diaminopropane) modified with 40 mol % of glycidol        suspended in 0.9% NaCl,    -   1 mg/kg ofloxacin,    -   3 mg/kg ofloxacin, and    -   5 mL/kg vehicle (0.9% NaCl).

Mortality was recorded once daily for 7 days and an increase of survivalrelative to vehicle control group was evaluated.

Table 4 displays the results against MRSA for the test compounds.

TABLE 4 MRSA Activity Survival Animals Survival Increase Treatment DoseDosed (N) (n/N) (%) Vehicle   5 mL/kg 10 0/10 — Poly(4,4-trimethylene0.2 mg/kg 10 1/10 10% dipiperidinebispropanoic acid-   5 mg/kg 10 6/10 60%* diaminopropane) modified with 40 mol % of glycidol *Survivalincrease ≧50% indicates significant anti-microbial effect

Example 2-2(b) E. coli

Five groups of 10 male mice were inoculated intraperitoneally with aLD₉₀₋₁₀₀ of E. coli (2.20×10⁵ CFU/mouse) suspended in 0.5 mL of BHIbroth containing 5% mucin. One hour after bacteria inoculation, groupsof 10 animals were intraperitoneally administered one of the following:

-   -   0.2 mg/kg poly(4,4-trimethylene dipiperidinebispropanoic        acid-diaminopropane) modified with 40 mol % of glycidol        suspended in 0.9% NaCl,    -   5 mg/kg poly(4,4-trimethylene dipiperidinebispropanoic        acid-diaminopropane) modified with 40 mol % of glycidol        suspended in 0.9% NaCl,    -   0.3 mg/kg gentamicin,    -   1 mg/kg gentamicin, and    -   5 mg/kg vehicle (0.9% NaCl).

Mortality was recorded once daily for 7 days and an increase of survivalrelative to vehicle control group was evaluated.

Table 5 displays the results against E. coli for the test compounds.

TABLE 5 E. coli Activity Survival Animals Survival Increase TreatmentDose Dosed (N) (n/N) (%) Vehicle   5 mL/kg 10 0/10 —Poly(4,4-trimethylene 0.2 mg/kg 10 0/10 0% dipiperidinebispropanoicacid-   5 mg/kg 10 8/10 80%* diaminopropane) modified with 40 mol% ofglycidol *Survival increase ≧50% indicates significant anti-microbialeffect

The test compound, poly(4,4-trimethylene dipiperidinebispropanoicacid-diaminopropane) modified with 40 mol % of glycidol, affordedsignificant anti-microbial protection, exhibiting 60% and 80% increasein survival rate in MRSA and E. coli infected mouse models.

Example 2-3 Efficacy—Mucositis

The goal of this study was to examine the role of schedule and route ofadministration on the observed efficacy of poly(4,4-trimethylenedipiperidinebispropanoic acid-diaminopropane) (1 mg/mL) on thefrequency, severity and duration of oral mucositis induced by acuteradiation. Male LVG Syrian Golden Hamsters, aged 5 to 6 weeks with anaverage body weight of 86.3 g at study commencement were used toevaluate the activity of each compound against radiation induced oralmucositis. Study endpoints were mucositis score, weight change andsurvival.

Male Syrian Golden Hamsters were randomly and prospectively divided intotreatment groups of seven (7) animals per group (test article) and onegroup of ten (10) animals (control).

On day 0, all animals were given an acute radiation dose of 40 Gydirected to their left buccal cheek pouch. On day 0, animals were dosedtopically once. From day 0 to day 20, 0.5 mL doses were appliedtopically to the left buccal pouch three times per day.

To evaluate mucositis severity, animals were anesthetized with aninhalation anesthetic, and the left cheek pouch everted. Mucositis wasscored visually by comparison to a validated photographic scale; thescale ranges from 0 for normal, to 5 for severe ulceration. Adescriptive version of the mucositis scoring scale used in this study ispresented in Table 6.

TABLE 6 Mucositis Scoring Scale Score Description: 0 Pouch completelyhealthy. No erythema or vasodilation. 1 Light to severe erythema andvasodilation. No erosion of mucosa. 2 Severe erythema and vasodilation.Erosion of superficial aspects of mucosa leaving denuded areas.Decreased stippling of mucosa. 3 Formation of off-white ulcers in one ormore places. Ulcers may have a yellow/gray appearance due topseudomembrane formation. Cumulative size of ulcers should equal about ¼of the pouch. Severe erythema and vasodilation. 4 Cumulative size ofulcers should equal about ½ of the pouch. Loss of pliability. Severeerythema and vasodilation. 5 Virtually all of pouch is ulcerated. Lossof pliability (pouch can only partially be extracted from mouth.

A score of 1 or 2 represent a mild stage of injury, a score of 3, 4 or 5indicates moderate to severe mucositis. Following visual scoring, adigital photograph was taken of each animal's mucosa using astandardized technique. At the conclusion of the experiment, all imageswere randomly numbered and graded in blinded fashion by at least twoindependent trained observers using the above-described scale (blindedscoring).

Animal deaths were evaluated during the course of the study. In themodel, deaths are most commonly attributable to adverse effectsassociated with anesthesia typically occurring at the time of radiation,or toxicity of the experimental compound. There were no deathsassociated with the experimental compounds.

Weight change was also evaluated as it represents a secondary method ofexamining potential toxicities of experimental treatments. Animals wereweighed daily throughout the study; weight changes were similar in allgroups. The mean percent weight gain during the study is provided inTable 7.

To evaluate the significance of these differences, the mean area underthe curve (AUC) was calculated for each animal from the percent weightgain data, and the means and standard errors were plotted. Using a oneway ANOVA, no statistically significant difference in weight change wasobserved in any of the groups.

To evaluate efficacy, the mean group mucositis scores were compared tothe control group in each experiment. A clinical mucositis score of 3 inhamsters indicates the presence of an ulcer. Ulceration is the point inthe development of mucositis where the physical integrity of the oralmucosa is breached. In the clinic, a patient presenting with severe oralulcerations may require hospitalization for analgesic, narcotic and/orantibiotic therapies or fluid support. The average cost to thehealthcare system is significant. Advanced mucositis in humans (withulcerative sores, correlating to a score of 3 or greater) often requiresthe interruption of therapy for patients receiving radiation and, ifsepsis occurs, these patients risk death. A therapeutic thatsignificantly reduces the time that a patient with oral mucositis hadulcers would be of great value to the clinician. The cumulative numberof days that an animal had a score of 3 or greater was determined due toits clinical significance.

The significance of group differences in scores of 3 or greater wasdetermined using Chi-squared (χ²) difference analysis for the totalnumber of animal days with a score of 3 or higher over the course of theentire study; these results are presented in Table 7. The severity andcourse of mucositis was favorably attenuated the in thepoly(4,4-trimethylene dipiperidinebispropanoic acid-diaminopropane)group.

TABLE 7 Mucositis Safety and Efficacy % % Weight Animal Days Dose Gainwith Mucositis Group (Concentration) (Days 0 to 20) Score ≧ 3 Control0.5 mL 41.6 41.3 topical, tid Poly(4,4-trimethylene 0.5 mL 34.2 28.6dipiperidinebispropanoic (1 mg/mL) acid-diaminopropane), topical, tid

Example 3 Synthesis of Amine Functional Polyamides Example 3-1 Synthesisof 4,4′-trimethylene dipiperidine bispropanoic acetate

To 5.0 g of 4,4′-trimethylene dipiperidine in 20 mL of methanol solution(20 mL), 4.6 g of methyl acrylate was added drop-wise. The resultingreaction mixture was stirred at room temperature for 16 hours. Thesolvent was removed under reduced pressure and the residue was purifiedby column chromatography using a gradient solvent system comprising offrom 100% hexane to 100% ethyl acetate. Removal of the solvent underreduced pressure yielded 7 g of the desired product as a white solid.

Example 3-2 Synthesis of 4,4′-dipiperidine bispropanoic acetate

To 10.0 g of 4,4′-dipiperidine HCl dissolved in 80 mL of methanol wasadded 12.6 g of potassium carbonate. The reaction mixture was stirred atroom temperature for 3 hours, at which time 8.03 g of methyl acrylatewas added slowly. The resulting reaction solution was then stirred atroom temperature for 18 hours. The reaction mixture was filtered and thefiltrate was evaporated to dryness under reduced pressure. The residuewas treated with 300 mL of ethyl acetate. The resulting suspension wasstirred at room temperature for 2 hours followed by filtration. Thefiltrate was evaporated to dryness under reduced pressure. The resultingmass was dried at room temperature under the vacuum to give 11.34 g ofthe desired product as an off white solid.

Example 3-3 Synthesis of Piperazine Bispropanoic Acetate

To 10 g of piperazine hexahydate dissolved in 40 mL of methanol wasadded 9.97 g of methyl acrylate in a drop-wise manner. The reactionmixture was stirred at room temperature for 18 hours. At the end of thistime, the reaction mixture was evaporated to dryness under reducedpressure. The residue was recrystallized from hexane/methylene chloride(1:1 v/v). After filtration and drying at room temperature under reducedpressure, 12.2 g of the desired product was obtained as a white solid.

Example 3-4 Synthesis of 1,1′-diacryl-4,4′-trimethylene dipiperidine

To 3.8 g of acryloyl chloride dissolved in 50 mL of dichloromethane wasadded a solution of 4.0 g of 4,4-trimethylene dipiperidine dissolved in20 mL dichloromethane in a drop-wise manner at 0° C. To this solutionwas added 4.23 g of triethyl amine slowly with a syringe. The resultingreaction mixture was stirred for 18 hours and was allowed to warm toroom temperature. The reaction mixture was filtered and the filtrate wascollected. After removing the solvent under reduced pressure, theresidue was treated with 100 mL of ethyl acetate. The solution wasextracted with 1M HCl (1×100 mL), saturated NaHCO₃ (2×100 mL), andfinally with brine (2×100 mL). The organic layer was collected and driedover Na₂SO₄. After filtration, the filtrate was evaporated to drynessunder reduced pressure. The residue was purified by columnchromatography using a gradient solvent system from 100% hexane to 100%ethyl acetate. Upon removal of the solvent, 3 g of the desired productwas obtained as viscous oil.

Example 3-5 Synthesis of 2,2′-bipyrrolidine bispropanoic acetate

To a solution of 5 g of 2,2′-bipyrrolidine in 20 mL of methanol wasadded 6.9 g of methyl acrylate (6.9 g, 80 mmol) in a drop-wise manner.The resulting reaction mixture was stirred at room temperature for 16hours. The reaction mixture was evaporated to dryness yielding 10 g ofthe desired product as viscous oil.

Example 3-6 Synthesis of poly(4,4′-trimethylene dipiperidinebispropanoic acid-co-1,3-diamino propane)

The reaction mixture consisting of 1 g of 4,4′-trimethylene dipiperidinebispropanoic acetate (Example 3-1) and 0.387 g of 1,3-diamino propanewas heated at 100° C. under nitrogen atmosphere for 18 hours. Theresulting product was dissolved in 5 mL of dichloromethane and waspoured into 50 mL of ethyl acetate. After filtering off the solvent, theresidue was dissolved in 20 mL of deionized (DI) water. The pH of thesolution was brought to 2 by addition of HCl. The resulting solution wasdialyzed against DI water for 24 hours using a dialysis membrane ofmolecular weight cut off of 1000 Dalton. The solution remaining in thedialysis bag was dried by lyophilization yielding 90 mg of the desiredproduct as a light yellow solid.

Example 3-7 Synthesis of poly(4,4′-trimethylene dipiperidinebispropanoic acid-co-diamino ethane)

The reaction mixture containing 0.5 g of 4,4′-trimethylene dipiperidinebispropanoic acetate (Example 3-1) and 0.157 g of diamino ethane wasstirred at 100° C. under nitrogen atmosphere for 18 hours. The resultingproduct was dissolved in 5 mL of dichloromethane and poured into 50 mLof ethyl acetate. The precipitate was isolated by filtration and wasdissolved in 20 mL of DI water. After adjusting the pH of the solutionto 2, it was dialyzed against DI water using a dialysis membrane ofmolecular weight cut off of 1000 Dalton. The solution remaining in thedialysis membrane was lyophilized to dryness yielding 50 mg of thedesired product as a light yellow solid.

Example 3-8 Synthesis of poly(4,4′-trimethylene dipiperidinebispropanoic acid-co-1,4-diamino butane)

The reaction mixture containing 0.5 g of 4,4′-trimethylene dipiperidinebispropanoic acetate and 0.23 g of 1,4-diamino butane was stirred at100° C. under nitrogen atmosphere for 18 hours. The resulting productwas dissolved in 5 mL of CH₂Cl₂ and then precipitated in 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 60 mg of the desired product as alight yellow solid.

Example 3-9 Synthesis of poly(4,4′-trimethylene dipiperidinebispropanoic acid-co-1,2-bis(2-aminoethoxy)ethane

The reaction mixture containing 0.5 g of 4,4′-trimethylene dipiperidinebispropanoic acetate and 0.26 g of 1,2-bis(2-aminoethoxy)ethane wasstirred at 100° C. under nitrogen atmosphere for 18 hours. The resultingproduct was dissolved in 5 mL of dichloromethane and poured into 50 mLof ethyl acetate. The precipitate was isolated by filtration and wasdissolved in 20 mL of DI water. After adjusting the pH of the solutionto 2, it was dialyzed against DI water using a dialysis membrane ofmolecular weight cut off of 1000 Dalton. The solution remaining in thedialysis membrane was lyophilized to dryness yielding 60 mg of thedesired product as a light yellow solid.

Example 3-10 Synthesis of poly(4,4′-trimethylene dipiperidinebispropanoic acid-co-1,4-bis(aminomethyl)benzene

The reaction mixture containing 0.5 g of 4,4′-trimethylene dipiperidinebispropanoic acetate and 0.7 g of 1,4-bis(aminomethyl)benzene (0.7 g,5.1 mmol) was stirred at 100° C. under nitrogen atmosphere for 18 hours.The resulting product was dissolved in 5 mL of dichloromethane andpoured into 50 mL of ethyl acetate. The precipitate was isolated byfiltration and was dissolved in 20 mL of DI water. After adjusting thepH of the solution to 2, it was dialyzed against DI water using adialysis membrane of molecular weight cut off of 1000 Dalton. Thesolution remaining in the dialysis membrane was lyophilized to drynessyielding 40 mg of the desired product as a light yellow solid.

Example 3-11 Synthesis of poly(4,4′-trimethylene dipiperidinebispropanoic acid-co-2,2′diamino diethylamine

The reaction mixture containing 0.5 g of 4,4′-trimethylene dipiperidinebispropanoic acetate and 0.35 g of 2,2′diamino diethylamine was stirredat 100° C. under nitrogen atmosphere for 18 hours. The resulting productwas dissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 63 mg of the desired product as alight yellow solid.

Example 3-12 Synthesis of poly(4,4′-trimethylene dipiperidinebispropanoic acid-co-N-methyl-2,2′diamino diethylamine

The reaction mixture containing 1 g of 4,4′-trimethylene dipiperidinebispropanoic acetate and 0.61 g of N-methyl-2,2′diamino diethylamine(0.61 g, 5.2 mmol) was stirred at 100° C. under nitrogen atmosphere for18 hours. The resulting product was dissolved in 5 mL of dichloromethaneand poured into 50 mL of ethyl acetate. The precipitate was isolated byfiltration and was dissolved in 20 mL of DI water. After adjusting thepH of the solution to 2, it was dialyzed against DI water using adialysis membrane of molecular weight cut off of 1000 Dalton. Thesolution remaining in the dialysis membrane was lyophilized to drynessyielding 130 mg of the desired product as a light yellow solid.

Example 3-13 Synthesis of poly(4,4′-trimethylene dipiperidinebispropanoic acid-co-N-(3-aminopropyl)-1,3-propane diamine

The reaction mixture containing 1 g of 4,4′-trimethylene dipiperidinebispropanoic acetate and 0.68 g of N-(3-aminopropyl)-1,3-propane diamine(0.68 g, 5.2 mmol) was stirred at 100° C. under nitrogen atmosphere for18 hours. The resulting product was dissolved in 5 mL of dichloromethaneand poured into 50 mL of ethyl acetate. The precipitate was isolated byfiltration and was dissolved in 20 mL of DI water. After adjusting thepH of the solution to 2, it was dialyzed against DI water using adialysis membrane of molecular weight cut off of 1000 Dalton. Thesolution remaining in the dialysis membrane was lyophilized to drynessyielding 180 mg of the desired product as a light yellow solid.

Example 3-14 Synthesis of poly(4,4′-trimethylene dipiperidinebispropanoic acid-co-3,3′-diamino-N-methyl dipropylamine

The reaction mixture containing 1 g of 4,4′-trimethylene dipiperidinebispropanoic acetate and 0.76 g of 3,3′-diamino-N-methyl dipropylaminewas stirred at 100° C. under nitrogen atmosphere for 18 hours. Theresulting product was dissolved in 5 mL of dichloromethane and pouredinto 50 mL of ethyl acetate. The precipitate was isolated by filtrationand was dissolved in 20 mL of DI water. After adjusting the pH of thesolution to 2, it was dialyzed against DI water using a dialysismembrane of molecular weight cut off of 1000 Dalton. The solutionremaining in the dialysis membrane was lyophilized to dryness yielding110 mg of the desired product as a light yellow solid.

Example 3-15 Synthesis of poly(4,4′-trimethylene dipiperidinebispropanoic acid-co-1,3-diamino-2-propanol

The reaction mixture containing 1 g of 4,4′-trimethylene dipiperidinebispropanoic acetate and 0.47 g of 1,3-diamino-2-propanol (0.47 g, 5.2mmol) was stirred at 100° C. under nitrogen atmosphere for 18 hours. Theresulting product was dissolved in 5 mL of dichloromethane and pouredinto 50 mL of ethyl acetate. The precipitate was isolated by filtrationand was dissolved in 20 mL of DI water. After adjusting the pH of thesolution to 2, it was dialyzed against DI water using a dialysismembrane of molecular weight cut off of 1000 Dalton. The solutionremaining in the dialysis membrane was lyophilized to dryness yielding60 mg of the desired product as a light yellow solid.

Example 3-16 Synthesis of poly(4,4′-trimethylene dipiperidinebispropanoic acid-co-4-(4-amino-butoxyl)-butyl amine

4-(4-amino-butoxyl)-butyl amine HCl salt (1 g) was dissolved in 20 mL ofmethanol. To this solution 0.72 g of aqueous sodium hydroxide solution(50% w/w)) was added. The reaction mixture was stirred at roomtemperature for 1 hour. After filtering off the solids, the filtrate wasevaporated to dryness. The residue was treated with 20 mL of ethanol.The reaction mixture was filtered and the filtrate was evaporated todryness yielding 0.55 g of an off white solid. This solid was combinedwith 0.75 g of 4,4′-trimethylene dipiperidine bispropanoic acetate andthe resulting reaction mixture was stirred at 100° C. under nitrogenatmosphere for 18 hours. The resulting product was dissolved in 5 mL ofdichloromethane and poured into 50 mL of ethyl acetate. The precipitatewas isolated by filtration and was dissolved in 20 mL of DI water. Afteradjusting the pH of the solution to 2, it was dialyzed against DI waterusing a dialysis membrane of molecular weight cut off of 1000 Dalton.The solution remaining in the dialysis membrane was lyophilized todryness yielding 90 mg of the desired product as a light yellow solid.

Example 3-17 Synthesis of poly(4,4′-trimethylene dipiperidinebispropanoic acid-co-3,5-diamino-1,2,4-triazol

The reaction mixture containing 1 g of 4,4′-trimethylene dipiperidinebispropanoic acetate and 0.31 g of 3,5-diamino-1,2,4-triazole wastreated with 1 mL of DMSO. The resulting reaction mixture was stirred at100° C. under nitrogen atmosphere for 18 hours. The resulting productwas dissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 10 mg of the desired product as alight yellow solid.

Example 3-18 Synthesis of poly(piperazine bispropanoic acid-co-diaminoethane)

The reaction mixture containing 1 g of piperazine bispropanoic acetate(Example 3-3) and 0.47 g of diamino ethane was stirred at 100° C. undernitrogen atmosphere for 18 hours. The resulting product was dissolved in5 mL of dichloromethane and poured into 50 mL of ethyl acetate. Theprecipitate was isolated by filtration and was dissolved in 20 mL of DIwater. After adjusting the pH of the solution to 2, it was dialyzedagainst DI water using a dialysis membrane of molecular weight cut offof 1000 Dalton. The solution remaining in the dialysis membrane waslyophilized to dryness yielding 10 mg of the desired product as a lightyellow solid.

Example 3-19 Synthesis of poly(piperazine bispropanoicacid-co-1,3-diamino propane)

The reaction mixture containing 1 g of piperazine bispropanoic acetate(Example 3-3) and 0.5 g of 1,3-diamino propane was stirred at 100° C.under nitrogen atmosphere for 18 hours. The resulting product wasdissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 30 mg of the desired product as alight yellow solid.

Example 3-20 Synthesis of poly(piperazine bispropanoicacid-co-1,4-diamino butane)

The reaction mixture containing 1 g of piperazine bispropanoic acetate(Example 3-3) and 0.6 g of 1,4-diamino butane was stirred at 100° C.under nitrogen atmosphere for 18 hours. The resulting product wasdissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 60 mg of the desired product as alight yellow solid.

Example 3-21 Synthesis of poly(piperazine bispropanoicacid-co-1,2-bis(2-aminoethoxy)ethane

The reaction mixture containing 1 g of piperazine bispropanoic acetate(Example 3-3) and 1.15 g of 1,2-bis(2-aminoethoxy)ethane was stirred at100° C. under nitrogen atmosphere for 18 hours. The resulting productwas dissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 30 mg of the desired product as alight yellow solid.

Example 3-22 Synthesis of poly(piperazine bispropanoicacid-co-2,2′diamino diethylamine

The reaction mixture containing 1 g of piperazine bispropanoic acetate(Example 3-3) and 0.8 g of 2,2′-diamino diethylamine was stirred at 100°C. under nitrogen atmosphere for 18 hours. The resulting product wasdissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 60 mg of the desired product as alight yellow solid.

Example 3-23 Synthesis of poly(piperazine bispropanoicacid-co-N-methyl-2,2′diamino diethylamine

The reaction mixture containing 1 g of piperazine bispropanoic acetate(Example 3-3) and 0.9 g of N-methyl-2,2′-diamino diethylamine wasstirred at 100° C. under nitrogen atmosphere for 18 hours. The resultingproduct was dissolved in 5 mL of dichloromethane and poured into 50 mLof ethyl acetate. The precipitate was isolated by filtration and wasdissolved in 20 mL of DI water. After adjusting the pH of the solutionto 2, it was dialyzed against DI water using a dialysis membrane ofmolecular weight cut off of 1000 Dalton. The solution remaining in thedialysis membrane was lyophilized to dryness yielding 50 mg of thedesired product as a light yellow solid.

Example 3-24 Synthesis of poly(piperazine bispropanoicacid-co-N-(3-aminopropyl)-1,3-propane diamine

The reaction mixture containing 1 g of piperazine bispropanoic acetate(Example 3-3) and 1.02 g of N-(3-aminopropyl)-1,3-propane diamine wasstirred at 100° C. under nitrogen atmosphere for 18 hours. The resultingproduct was dissolved in 5 mL of dichloromethane and poured into 50 mLof ethyl acetate. The precipitate was isolated by filtration and wasdissolved in 20 mL of DI water. After adjusting the pH of the solutionto 2, it was dialyzed against DI water using a dialysis membrane ofmolecular weight cut off of 1000 Dalton. The solution remaining in thedialysis membrane was lyophilized to dryness yielding 90 mg of thedesired product as a light yellow solid.

Example 3-25 Synthesis of poly(piperazine bispropanoicacid-co-3,3′-diamino-N-methyl dipropylamine

The reaction mixture containing 1 g of piperazine bispropanoic acetate(Example 3-3) and 1.12 g of 3,3′-diamino-N-methyl dipropylamine wasstirred at 100° C. under nitrogen atmosphere for 18 hours. The resultingproduct was dissolved in 5 mL of dichloromethane and poured into 50 mLof ethyl acetate. The precipitate was isolated by filtration and wasdissolved in 20 mL of DI water. After adjusting the pH of the solutionto 2, it was dialyzed against DI water using a dialysis membrane ofmolecular weight cut off of 1000 Dalton. The solution remaining in thedialysis membrane was lyophilized to dryness yielding 120 mg of thedesired product as a light yellow solid.

Example 3-26 Synthesis of poly(4,4′-dipiperidine bispropanoicacid-co-diamino ethane

The reaction mixture containing 1 g of 4,4′-dipiperidine bispropanoicacetate (Example 3-2) and 0.31 g of diamino ethane was stirred at 100°C. under nitrogen atmosphere for 18 hours. The resulting product wasdissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 90 mg of the desired product as alight yellow solid.

Example 3-27 Synthesis of poly(4,4′-dipiperidine bispropanoicacid-co-1,3-diamino propane

The reaction mixture containing 1 g of 4,4′-dipiperidine bispropanoicacetate (Example 3-2) and 0.38 g of 1,3-diamino propane was stirred at100° C. under nitrogen atmosphere for 18 hours. The resulting productwas dissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 60 mg of the desired product as alight yellow solid.

Example 3-28 Synthesis of poly(4,4′-dipiperidine bispropanoicacid-co-1,4-diamino butane

The reaction mixture containing 1 g of 4,4′-dipiperidine bispropanoicacetate (Example 3-2) and 0.45 g of 1,4-diamino butane was stirred at100° C. under nitrogen atmosphere for 18 hours. The resulting productwas dissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 90 mg of the desired product as alight yellow solid.

Example 3-29 Synthesis of poly(4,4′-dipiperidine bispropanoicacid-co-1,2-bis(2-aminoethoxy)ethane

The reaction mixture containing 1 g of 4,4′-dipiperidine bispropanoicacetate (Example 3-2) and 0.76 g of 1,2-bis(2-aminoethoxy)ethane wasstirred at 100° C. under nitrogen atmosphere for 18 hours. The resultingproduct was dissolved in 5 mL of dichloromethane and poured into 50 mLof ethyl acetate. The precipitate was isolated by filtration and wasdissolved in 20 mL of DI water. After adjusting the pH of the solutionto 2, it was dialyzed against DI water using a dialysis membrane ofmolecular weight cut off of 1000 Dalton. The solution remaining in thedialysis membrane was lyophilized to dryness yielding 100 mg of thedesired product as a light yellow solid.

Example 3-30 Synthesis of poly(4,4′-dipiperidine bispropanoicacid-co-2,2′diamino diethylamine

The reaction mixture containing 1 g of 4,4′-dipiperidine bispropanoicacetate and 0.45 g of 2,2′diamino diethylamine was stirred at 100° C.under nitrogen atmosphere for 18 hours. The resulting product wasdissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 310 mg of the desired product as alight yellow solid.

Example 3-31 Synthesis of poly(4,4′-dipiperidine bispropanoicacid-co-N-methyl-2,2′diamino diethylamine

The reaction mixture containing 1 g of 4,4′-dipiperidine bispropanoicacetate and 0.52 g of N-methyl-2,2′diamino diethylamine was stirred at100° C. under nitrogen atmosphere for 18 hours. The resulting productwas dissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 480 mg of the desired product as alight yellow solid.

Example 3-32 Synthesis of poly(4,4′-dipiperidine bispropanoicacid-co-N-(3-aminopropyl)-1,3-propane diamine

The reaction mixture containing 1 g of 4,4′-dipiperidine bispropanoicacetate and 0.58 g of N-(3-aminopropyl)-1,3-propane diamine was stirredat 100° C. under nitrogen atmosphere for 18 hours. The resulting productwas dissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 540 mg of the desired product as alight yellow solid.

Example 3-33 Synthesis of poly(4,4′-dipiperidine bispropanoicacid-co-3,3′-diamino-N-methyl dipropylamine

The reaction mixture containing 1 g of 4,4′-dipiperidine bispropanoicacetate and 0.64 g of 3,3′-diamino-N-methyl dipropylamine was stirred at100° C. under nitrogen atmosphere for 18 hours. The resulting productwas dissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 420 mg of the desired product as alight yellow solid.

Example 3-34 Synthesis of Poly(1,1′-diacryl-4,4′-trimethylenedipiperidine-co-1,3-diaminopropane

The reaction mixture containing 1 g of 1,1′-diacryl-4,4′-trimethylenedipiperidine, 0.35 g 1,3-diamino propane and 1 mL of methanol wasstirred at room temperature for 18 hours. The resulting product wasdissolved in 5 mL of dichloromethane and poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 640 mg of the desired product as alight yellow solid.

Example 3-35 Synthesis of poly(1,1′-diacryl-4,4′-trimethylenedipiperidine-co-N,N′-dimethyl-1,3-propanediamine

The reaction mixture containing 1 g of 1,1′-diacryl-4,4′-trimethylenedipiperidine, 0.36 g of N,N′-dimethyl-1,3-propanediamine and 1 mL ofmethanol was stirred at 60° C. for 24 hours. The solvent was removedunder reduced pressure and the residue was dissolved in 20 mL of DIwater. The pH of the solution was adjusted to 2 by adding HCl. Thepolymer solution dialyzed against DI water using a dialysis membrane ofmolecular weight cut off of 1000 Dalton. The solution remaining in thedialysis membrane was lyophilized to dryness yielding 180 mg of thedesired product as a light yellow solid.

Example 3-36 Synthesis of poly(1,1′-diacryl-4,4′-trimethylenedipiperidine-co-4,4′-trimethylene dipiperidine

The reaction mixture containing 1 g of 1,1′-diacryl-4,4′-trimethylenedipiperidine, 0.99 g of 4,4′-trimethylene dipiperidine, 1 mL of methanolwas stirred at 60° C. for 12 hours. The resulting product was dissolvedin 5 mL of dichloromethane and poured into 50 mL of ethyl acetate. Theprecipitate was isolated by filtration and was dissolved in 20 mL of DIwater. After adjusting the pH of the solution to 2, it was dialyzedagainst DI water using a dialysis membrane of molecular weight cut offof 1000 Dalton. The solution remaining in the dialysis membrane waslyophilized to dryness yielding 220 mg of the desired product as a lightyellow solid.

Example 3-37 Synthesis of poly(1,1′-diacryl-4,4′-trimethylenedipiperidine-co-piperazine

The reaction mixture containing 1 g of 1,1′-diacryl-4,4′-trimethylenedipiperidine, 0.91 g of piperazine hexahydrate and 1 mL of methanol wasstirred at 60° C. for 12 hours. The resulting product was dissolved in 5mL of dichloromethane and poured into 50 mL of ethyl acetate. Theprecipitate was isolated by filtration and was dissolved in 20 mL of DIwater. After adjusting the pH of the solution to 2, it was dialyzedagainst DI water using a dialysis membrane of molecular weight cut offof 1000 Dalton. The solution remaining in the dialysis membrane waslyophilized to dryness yielding 80 mg of the desired product as a lightyellow solid.

Example 3-38 Synthesis of poly(1,1′-diacryl-4,4′-trimethylenedipiperidine-co-4,4′-bipiperidine

A solution containing 1.14 g of 4,4′-dipiperidine HCl and 5 mL ofmethanol was treated with 1.14 g of potassium carbonate. The reactionmixture was stirred at room temperature for 2 hours. The reactionmixture was filtered and the filtrate was combined with 1 g of1,1′-diacryl-4,4′-trimethylene dipiperidine dissolved in 3 mL ofmethanol. The resulting reaction mixture was stirred at 60° C. for 15hours. The resulting product was poured into 50 mL of ethyl acetate. Theprecipitate was isolated by filtration and was dissolved in 20 mL of DIwater. After adjusting the pH of the solution to 2, it was dialyzedagainst DI water using a dialysis membrane of molecular weight cut offof 1000 Dalton. The solution remaining in the dialysis membrane waslyophilized to dryness yielding 140 mg of the desired product as a lightyellow solid.

Example 3-39 Synthesis of poly(1,1′diacryl-4,4′-trimethylenedipiperidine-co-histamine)

The reaction mixture containing 1 g of 1,1′-diacryl-4,4′-trimethylenedipiperidine, 0.5 g of histamine and 1 mL of methanol was stirred at 60°C. for 18 hours. The resulting product was poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 120 mg of the desired product as alight yellow solid.

Example 3-40 Synthesis of poly(1,1′diacryl-4,4′-trimethylenedipiperidine-co-3-(dimethylamino)-1-propylamine)

The reaction mixture containing 1 g of 1,1′-diacryl-4,4′-trimethylenedipiperidine, 0.53 g of 3-(dimethylamino)-1-propylamine and 1 mL ofmethanol was stirred at 50° C. for 10 hours. The resulting product waspoured into 50 mL of ethyl acetate. The precipitate was isolated byfiltration and was dissolved in 20 mL of DI water. After adjusting thepH of the solution to 2, it was dialyzed against DI water using adialysis membrane of molecular weight cut off of 1000 Dalton. Thesolution remaining in the dialysis membrane was lyophilized to drynessyielding 1 g of the desired product as a light yellow solid.

Example 3-41 Synthesis of poly(1,1′diacryl-4,4′-trimethylenedipiperidine-co-propyl amine

The reaction mixture containing 0.64 g of 1,1′-diacryl-4,4′-trimethylenedipiperidine, 0.35 g of propyl amine, and 1 mL methanol was stirred at60° C. for 20 hours. The resulting product was poured into 50 mL ofethyl acetate. The precipitate was isolated by filtration and wasdissolved in 20 mL of DI water. After adjusting the pH of the solutionto 2, it was dialyzed against DI water using a dialysis membrane ofmolecular weight cut off of 1000 Dalton. The solution remaining in thedialysis membrane was lyophilized to dryness yielding 740 mg of thedesired product as a light yellow solid.

Example 3-42 Synthesis of poly(1,1′diacryl 4,4′-trimethylenedipiperidine-co-1-aminobutyl-3-carbamoyl pyridinium

The reaction mixture containing 0.5 g of 1,1′-diacryl-4,4′-trimethylenedipiperidine, 0.35 g of 1-aminobutyl-3-carbamoyl pyridinium, and 3 mL ofmethanol was stirred at 50° C. for 20 hours. The resulting product waspoured into 50 mL of ethyl acetate. The precipitate was isolated byfiltration and was dissolved in 20 mL of DI water. After adjusting thepH of the solution to 2, it was dialyzed against DI water using adialysis membrane of molecular weight cut off of 1000 Dalton. Thesolution remaining in the dialysis membrane was lyophilized to drynessyielding 20 mg of the desired product as a light yellow solid.

Example 3-43 Synthesis of poly(1,1′diacryl-4,4′-trimethylenedipiperidine-co-1-aminobutyl-3-carbamoylpyridinium)-co-4,4′-trimethylene dipiperidine bispropanoicacid-2-dydroxy-1,3-diamino propane)

The reaction mixture containing 1.0 g of 1,1′-diacryl-4,4′-trimethylenedipiperidine, 0.36 g of 1-aminobutyl-3-carbamoyl pyridinium, 0.27 g ofmono N-boc-1,3-diaminopropane, and 3 mL of methanol stirred at 50° C.for 20 hours. The reaction mixture was poured into 50 mL of ethylacetate. The precipitate was isolated by filtration. The residue waswashed with ethyl acetate (3×50 mL) and dried under reduced pressure.

Above product was dissolved in 5 mL of methanol and mixed with 0.5 g of4,4′-trimethylene dipiperidine bispropanoic acid and 0.25 mL ofconcentrated HCl. The resulting reaction mixture was stirred at 50° C.for 6 hours. The resulting product was poured into 50 mL of ethylacetate. The precipitate was isolated by filtration and was dissolved in20 mL of DI water. After adjusting the pH of the solution to 2, it wasdialyzed against DI water using a dialysis membrane of molecular weightcut off of 1000 Dalton. The solution remaining in the dialysis membranewas lyophilized to dryness yielding 210 mg of the desired product as alight yellow solid.

Example 3-44 Synthesis of poly(2,2′-bipyrrolidine bispropanoicacid-co-diamino ethane)

The reaction mixture containing 1.0 g of 2,2′-bipyrrolidine bispropanoicacetate and 0.38 g diamino ethane was stirred at 100° C. under nitrogenatmosphere for 20 hours. The resulting product was dissolved in 3 mL ofmethanol and poured into 50 mL of ethyl acetate. The precipitate wasisolated by filtration and was dissolved in 20 mL of DI water. Afteradjusting the pH of the solution to 2, it was dialyzed against DI waterusing a dialysis membrane of molecular weight cut off of 1000 Dalton.The solution remaining in the dialysis membrane was lyophilized todryness yielding 10 mg of the desired product as a light yellow solid.

Example 3-45 Synthesis of poly(2,2′-bipyrrolidine bispropanoicacid-co-1,3-diamino propane)

The reaction mixture containing 1.0 g of 2,2′-bipyrrolidine bispropanoicacetate and 0.47 g of 1,3-diamino propane was stirred at 100° C. undernitrogen atmosphere for 20 hours. The resulting product was dissolved in3 mL of methanol and poured into 50 mL of ethyl acetate. The precipitatewas isolated by filtration and was dissolved in 20 mL of DI water. Afteradjusting the pH of the solution to 2, it was dialyzed against DI waterusing a dialysis membrane of molecular weight cut off of 1000 Dalton.The solution remaining in the dialysis membrane was lyophilized todryness yielding 540 mg of the desired product as a light yellow solid.

Example 3-46 Synthesis of poly(2,2′-bipyrrolidine bispropanoicacid-co-1,3-diamino butane)

The reaction mixture containing 1.0 g of 2,2′-bipyrrolidine bispropanoicacetate and 0.56 g of 1,4-diamino butane was stirred at 100° C. undernitrogen atmosphere for 20 hours. The resulting product was dissolved in3 mL of methanol and poured into 50 mL of ethyl acetate. The precipitatewas isolated by filtration and was dissolved in 20 mL of DI water. Afteradjusting the pH of the solution to 2, it was dialyzed against DI waterusing a dialysis membrane of molecular weight cut off of 1000 Dalton.The solution remaining in the dialysis membrane was lyophilized todryness yielding 380 mg of the desired product as a light yellow solid.

Example 3-47 Synthesis of poly(2,2′-bipyrrolidine bispropanoicacid-co-1,5-diamino pentane)

The reaction mixture containing 1.0 g of 2,2′-bipyrrolidine bispropanoicacetate and 0.65 g of 1,5-diamino pentane was stirred at 100° C. undernitrogen atmosphere for 20 hours. The resulting product was dissolved in3 mL of methanol and poured into 50 mL of ethyl acetate. The precipitatewas isolated by filtration and was dissolved in 20 mL of DI water. Afteradjusting the pH of the solution to 2, it was dialyzed against DI waterusing a dialysis membrane of molecular weight cut off of 1000 Dalton.The solution remaining in the dialysis membrane was lyophilized todryness yielding 10 mg of the desired product as a light yellow solid.

Example 3-48 Synthesis of poly(2,2′-bipyrrolidine bispropanoicacid-co-1,6-diamino hexane)

The reaction mixture containing 1.0 g of 2,2′-bipyrrolidine bispropanoicacetate and 0.74 g of 1,6-diamino hexane was stirred at 100° C. undernitrogen atmosphere for 20 hours. The resulting product was dissolved in3 mL of methanol and poured into 50 mL of ethyl acetate. The precipitatewas isolated by filtration and was dissolved in 20 mL of DI water. Afteradjusting the pH of the solution to 2, it was dialyzed against DI waterusing a dialysis membrane of molecular weight cut off of 1000 Dalton.The solution remaining in the dialysis membrane was lyophilized todryness yielding 10 mg of the desired product as a light yellow solid.

Example 3-49 Synthesis of poly(4,4-Trimethylene dipiperidinebispropanoic acid-co-4-(1,2-diol)-1,4,7-triazaheptane) Example 3-49(a)Synthesis of 4-(1,2-diol)-1,4,7-triazaheptane

In 5 mL of ethanol 1 g of 1,7-bis-Boc-1,4,7-triazaheptane and 0.3 g ofglycidol were added and the reaction mixture was refluxed for 15 hours.The resulting product was purified by column chromatography usinggradient solvent system in the range of 100% hexane to 100% yielding 0.4g of 1,7-bis-boc-4-(1,2-diol)-1,4,7-triazaheptane. To 0.4 g of1,7-bis-boc-4-(1,2-diol)-1,4,7-triazaheptane dissolved in 2 mL ofmethanol was added 0.3 mL of concentrated HCl. The reaction mixture wasstirred at 50° C. for 24 hours. After removing the solvent under reducedpressure, the residue was dissolved in 10 mL of methanol:water (1:1v/v). To this solution was added 5.0 g of Amberlyst OH 26 resin. Afterstirring at room temperature for 3 hours, the resin was filtered off.The solvent was evaporated under reduced pressure. The resulting oil waslyophilized to dry to give 0.15 g of the desired product as a viscousliquid.

Example 3-49(b) Synthesis of poly(4,4-Trimethylene dipiperidinebispropanoic acid-co-4-(1,2-diol)-1,4,7-triazaheptane)

The reaction mixture containing 0.288 g of 4,4′-trimethylenedipiperidine bispropanoic acetate and 0.15 g of4-(1,2-diol)-1,4,7-triazaheptane (Example 3-49(a)) stirred at 100° C.for 18 hours. The resulting product was dissolved in 3 mL of methanoland poured into 50 mL of ethyl acetate. The precipitate was isolated byfiltration and was dissolved in 20 mL of DI water. After adjusting thepH of the solution to 2, it was dialyzed against DI water using adialysis membrane of molecular weight cut off of 1000 Dalton. Thesolution remaining in the dialysis membrane was lyophilized to drynessyielding 160 mg of the desired product as a light yellow solid.

Example 3-50 Synthesis of poly(4,4-trimethylene dipiperidinebispropanoic acid-co-4-(1,2-diol)-1,4,7-triazaheptane-co-1,3-diaminopropane)

The reaction mixture containing 0.25 g of 4,4′-trimethylene dipiperidinebispropanoic acetate, 0.09 g of 4-(1,2-diol)-1,4,7-triazaheptane(Example 3-49(a)) and 0.05 g of 1,3-diamino propane stirred at 100° C.for 18 hours. The resulting product was dissolved in 3 mL of methanoland poured into 50 mL of ethyl acetate. The precipitate was isolated byfiltration and was dissolved in 20 mL of DI water. After adjusting thepH of the solution to 2, it was dialyzed against DI water using adialysis membrane of molecular weight cut off of 1000 Dalton. Thesolution remaining in the dialysis membrane was lyophilized to drynessyielding 150 mg of the desired product as a light yellow solid.

Example 3-51 Synthesis of poly(4,4-Trimethylene dipiperidinebispropanoic acid-co-5-(1,2-diol)-1,5,9-triazanonane) Example 3-51(a)Synthesis of 5-(1,2-diol)-1,5,9-triazanonane

The reaction mixture containing 1.5 g of 1,9-Bis-BOC-1,5,9-triazanonane,0.34 g of glycidol, and 10 mL of ethanol was refluxed for 15 hours.After removal of the solvent, the residue was purified by columnchromatography using a gradient solvent system ranging from 100% hexaneto 100% ethyl acetate) yielding 0.7 g of1,9-bis-boc-5-(1,2-diol)-1,5,9-triazanonane. To 0.7 g of1,9-bis-boc-5-(1,2-diol)-1,5,9-triazanonane dissolved in 2 mL ofmethanol was added 0.25 mL of concentrated HCl and the reaction mixturestirred at 50° C. for 24 hours. After removal of the solvent underreduced pressure, the residue was dissolved in 10 mL of methanol/water(1:1) mixture and 5 g of Amberlyst OH 26 resin was added it. Afterstirring at room temperature for 3 hours, the resin was filtered off.The solvent was removed under reduced pressure and the residue waslyophilized to dryness yielding 0.28 g of the desired product as lightyellow oil.

Example 3-51(b) Synthesis of poly(4,4-Trimethylene dipiperidinebispropanoic acid-co-5-(1,2-diol)-1,5,9-triazanonane)

The reaction mixture containing 0.23 g of 4,4′-trimethylene dipiperidinebispropanoic acetate and 0.15 g of 5-(1,2-diol)-1,5,9-triazanonane wasstirred at 100° C. for 18 hours. The resulting reaction mixture wasdissolved in 5 mL of methanol and poured into 50 mL of ethyl acetate.After filtering off the solvent, the residue was dissolved in 20 mL ofDI water. The pH of the solution was adjusted to 2 by adding dilute HCland the solution subjected to centrifugation using with Microsepmembrane filter with a molecular weight cut off of 1000 Dalton. Thefraction with molecular weight higher than 1000 Dalton was collected andlyophilized to dryness yielding 100 mg of the desired product as a lightyellow solid.

Example 3-52 Synthesis of poly(4,4-trimethylene dipiperidinebispropanoic acid-co-5-(1,2-diol)-1,5,9-triazanonane-co-1,3-diaminopropane)

The reaction mixture containing 0.125 g 4,4′-trimethylene dipiperidinebispropanoic acetate (Example 3-1), 0.05 g of5-(1,2-diol)-1,5,9-triazanonane (Example 3-51(a)), and 0.3 g of1,3-diamino propane was stirred at 100° C. for 18 hours. The resultingreaction mixture was dissolved in 5 mL of methanol poured into 50 mL ofethyl acetate. After filtering off the solvent, the residue wasdissolved in 20 mL of DI water. The pH of the solution was adjusted to 2by adding dilute HCl and the solution subjected to centrifugation usingwith Microsep membrane filter with a molecular weight cut off of 1000Dalton. The fraction with molecular weight higher than 1000 Dalton wascollected and lyophilized to dryness yielding 90 mg of the desiredproduct as a light yellow solid.

Example 3-53 Synthesis of glycidol modified poly(4,4′-trimethylenedipiperidine bispropanoic acid-co-1,3-diamino propane)

To 0.26 g poly(4,4′-trimethylene dipiperidine bispropanoicacid-co-1,3-diamino propane) (Example 3-6) dissolved in 2 mL of ethanolwas added 16.5 mg of glycidol. The reaction mixture at 140° C. for 30minutes using a microwave reactor. The resulting reaction mixture waspoured into 50 mL of ethyl acetate. After filtration, the residue waswashed with ethyl acetate (3×50 mL). Subsequently, it was dissolved in10 mL of DI water and was subjected to centrifugation using withMicrosep membrane filter with a molecular weight cut off of 1000 Dalton.The fraction with molecular weight higher than 1000 Dalton was collectedand lyophilized to dryness yielding 126 mg of the desired product as alight yellow solid.

Example 3-54 Synthesis of Guanidine terminated poly(4,4′-trimethylenedipiperidine bispropanoic acid-co-1,3-diamino propane)

To 0.3 g of poly(4,4′-trimethylene dipiperidine bispropanoicacid-co-1,3-diamino propane) (Example 3-6) dissolved in 2 mL of methanolwas added 0.1 g of 1H-pyrazole-1-carboxamidine and 0.11 g ofN,N′-diisopropylethylamine. The reaction mixture was stirred at 60° C.for 8 hours. The resulting reaction mixture was poured into 50 mL ofethyl acetate. After filtration, the residue was washed with ethylacetate (3×50 mL). The resulting solid was dissolved in 2 mL of DI waterand was passed through a PD-10 Sephadex column. The desired fractionswere collected, lyophilized to dryness yielding 0.19 g of the polymer asa light yellow solid.

Example 3-55 Synthesis of Polyethylene glycol (PEG-4) terminatedpoly(4,4′-trimethylene dipiperidine bispropanoic acid-co-1,3-diaminopropane)

To 0.128 g of poly(4,4′-trimethylene dipiperidine bispropanoicacid-co-1,3-diamino propane) (Example 3-6) dissolved in 5 mL of methanolsolution was added 0.2 mL of triethyl amine followed by 0.075 g ofm-dPEG4-NHS ester. The reaction solution was stirred at room temperaturefor 22 hours. The resulting reaction mixture was poured into 50 mL ofethyl acetate. After filtration, the residue was washed with ethylacetate (5×50 mL). The residue was subsequently dissolved in 2 mL of DIwater and the pH of the resulting solution was adjusted to 2 usingdilute HCl was subjected to centrifugation using a Microsep membranefilter with a molecular weight cut off of 1000 Dalton. The fraction withmolecular weight higher than 1000 Dalton was collected and lyophilizedto dryness yielding 50 mg of the desired product as a light yellowsolid.

Example 356 Synthesis of Polyethylene glycol (PEG-12) terminatedpoly(4,4′-trimethylene dipiperidine bispropanoic acid-co-1,3-diaminopropane)

To 0.1 g of poly(4,4′-trimethylene dipiperidine bispropanoicacid-co-1,3-diamino propane) (Example 3-6) dissolved 5 mL of methanolwas added 0.2 mL of triethyl amine followed by 0.12 g of m-dPEG12-NHSester. The reaction solution was stirred at room temperature for 22hours. The resulting reaction mixture was poured into 50 mL of ethylacetate. After filtration, the residue was washed with ethyl acetate(5×50 mL). The residue was subsequently dissolved in 2 mL of DI waterand the pH of the resulting solution was adjusted to 2 using dilute HCl.was subjected to centrifugation using with Microsep membrane filter witha molecular weight cut off of 1000 Dalton. The fraction with molecularweight higher than 1000 Dalton was collected and lyophilized to drynessyielding 60 mg of the desired product as a light yellow solid.

Example 3-57 Synthesis of monodispersed polymer (heptamer) ofpoly(4,4′-trimethylene dipiperidine bispropanoic acid-co-1,3-diaminopropane) Example 3-57(a) Synthesis of 4,4′-trimethylene dipiperidinebispropanoic acid-1,3-diamino propane trimer

The reaction mixture containing 3 g of 4,4′-trimethylene dipiperidinebispropanoic acetate (Example 3-2) and 4.1 g of mono N-boc-1,3-diaminopropane was stirred at 100° C. for 18 hours. The resulting reactionmixture was purified by column chromatography using an amine modifiedsilica column and the gradient solvent system ranging from 100% hexaneto ethyl acetate/hexane (50/50)). The appropriate fraction was collectedand removal of the solvent under reduced pressure produced 2.6 g of4,4′-trimethylene dipiperidine bispropanoic acid-bis-BOC-1,3-diaminopropane.

To 0.55 g of 4,4′-trimethylene dipiperidine bispropanoicacid-bis-boc-1,3-diamino propane dissolved in 5 mL of methanol was added0.5 mL of concentrated HCl and the reaction mixture was stirred at 50°C. for 10 hours. After removal of the solvent under reduced pressure,the residue was dissolved in 10 mL of methanol/water (1:1) and wastreated with 5 g of Amberlyst OH 26 resin. After stirring at roomtemperature for 3 hours, the resin was filtered off. The filtrate wasevaporated dryness and the residue was lyophilized yielding 0.5 g of theproduct as a white solid.

Example 3-57(b) Synthesis of 1-BOC-4,4′-trimethylene-1′-propanoic acid

To 2 g of 1-BOC-4,4′-trimethylene-1′propanoic methyl ester, 0.9 g of 50wt % solution of aqueous sodium hydroxide was added and the reactionmixture was stirred at 60° C. for 15 hours. To this reaction mixture wasadded concentrated HCl until pH of the reaction reached 7.5. Thereaction mixture was evaporated to dryness and residue was lyophilizedto complete dryness. To this dry residue was added 10 mL ofdichloromethane and the resulting mixture was stirred at roomtemperature for 30 minutes. After filtering off the insoluble particles,the filtrate was evaporated to dryness to give 0.7 g of a white solidproduct.

Example 3-57(c) Synthesis of bis-boc-4,4′-trimethylene dipiperidinebispropanoic acid-1,3-diamino propane pentamer

To 90 mg of 1-boc-4,4′-trimethylene-1′-propanoic acid (Example 3-57(b))dissolved in 2 mL of dicloromethane/DMF (1:1 v/v) was added 38 mg of1,1-carbonyl diimidazole. After stirring at room temperature for 1 hour,0.05 g of 4,4′-trimethylene dipiperidine bispropanoic acid-1,3-diaminopropane trimer (Example 3-57(a)) was added to reaction mixture. Theresulting reaction mixture was stirred at room temperature for 20 hours.After removing the solvent under reduced pressure, the residue waspurified by column chromatography using an amine modified silica columnusing a gradient solvent system ranging from 100% ethyl acetate to ethylacetate/methanol (95/5)) yielding 80 mg of the product as a colorlessoil. This oil was dissolved 2 mL of methanol followed by addition of 0.5mL of concentrated HCl. The reaction mixture was stirred at 50° C. for10 hours. The solvent was evaporated removed under reduced pressure andthe residue was lyophilized to dry to yield 60 mg of the desired productas yellow viscous oil.

Example 3-57(d) Synthesis of poly(4,4′-trimethylene dipiperidinebispropanoic acid-co-1,3-diamino propane) heptamer

To 35 mg of 4,4′-trimethylene dipiperidine bispropanoic acid-1,3-diaminopropane pentamer (Example 3-57(c)) dissolved in 1 mL of methanol wasadded 0.08 mL of triethyl amine and 24 mg of boc-(3-acrylamido) propylamine. The reaction mixture was stirred at room temperature overnight.The reaction mixture was poured into 10 mL of ethyl acetate. The residuewas isolated by filtration and was washed with ethyl acetate (3×10 mL).The residue was dried at room temperature under reduced pressureyielding 40 mg of a white solid. To this solid residue was added 2 mL ofmethanol and 0.5 mL of concentrated HCl. The resulting reaction mixturewas added stirred at 50° C. for 10 hours. After removing the solventunder reduced pressure, residue was purified by preparative HPLCyielding 10 mg of the desired product as light yellow viscous oil.

The invention claimed is:
 1. A compound comprising the structure ofFormula (I):

wherein: i) m is 1, 2, or 3; ii) n is 0, 1, 2, or 3; iii) o is 1, 2, or3; iv) p is 0 or 1; v) r is 0 or 1; vi) q is an integer from 1 to 400;vii) Q^(x) is NH, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl; viii) Q^(y) isNH—R^(w), NH—CH₂—R_(w), (C₁-C₁₀)alkyl, or (C₆-C₁₄)aryl, wherein R^(w) isabsent or a (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₆-C₁₄)aryl, or(C₂-C₉)heteroaryl; ix) R^(x) and R^(y) are each independently apharmaceutically acceptable end group.
 2. The compound according toclaim 1 wherein n is
 0. 3. The compound according to claim 1 wherein nis
 1. 4. The compound according to claim 1 wherein n is
 2. 5. Thecompound according to claim 1 wherein n is
 3. 6. The compound accordingto claim 1 wherein p is
 0. 7. The compound according to claim 1 whereinp is
 1. 8. The compound according to claim 1 wherein r is
 0. 9. Thecompound according to claim 1 wherein r is
 1. 10. The compound accordingto claim 1 wherein p is 0 and r is
 0. 11. The compound according toclaim 1 wherein p is 1 and r is
 1. 12. The compound according to claim 1wherein n is 3; p is 1; and r is
 1. 13. The compound according to claim1 wherein n is 0; p is 1; and r is
 1. 14. The compound according toclaim 1 wherein n is 0; p is 0; and r is
 0. 15. The compound accordingto claim 11 wherein: i) Q^(x) is —NH; and ii) Q^(y) is NH—R^(w)—,wherein R^(w) is a (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₆-C₁₄)aryl, or(C₂-C₉)heteroaryl.
 16. The compound according to claim 12 wherein: i) mis 2; ii) o is 2; iii) Q^(x) is NH; and iv) Q^(y) is NH—R^(w)—, whereinR^(w) is a (C₃)alkyl.
 17. The compound according to claim 14 wherein: i)Q^(x) is NH; and ii) Q^(y) is N—R^(w), wherein R^(w) is absent or a(C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₆-C₁₄)aryl, or (C₂-C₉)heteroaryl.18. The compound according to claim 12 wherein: i) m is 2; ii) o is 2;iii) Q^(x) is NH; iv) Q^(y) is NH—R_(w)—, wherein R_(w) is a (C₃)alkylv) R^(x) is a guanidinium chloride group represented by Formula (B),

wherein b is 3; and vi) R^(y) is a guanidinium chloride grouprepresented by Formula (B),

wherein b is
 0. 19. The compound according to claim 1, wherein R^(x) andR^(y) are each independently H, (C₁-C₁₀)alkyl, (C₂-C₀)heteroalkyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,(C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, —O(O)C—(C₁-C₁₀)alkyl,(C₁-C₁₀)alkyl-COOH, (C₃-C₁₀)cycloalkyl-COOH, —(O)CH₃, —OH, amide, aguanidino group represented by Formula (A)

wherein a is an integer from 0 to 25, a guanidinium chloride grouprepresented by Formula (B),

wherein b is an integer from 0 to 25, a guanidinobenzene grouprepresented by Formula (C),

wherein c is an integer from 0 to 25, a dihydroxy group, represented byFormula (D),

wherein d is an integer from 0 to 25, or a polyethylene glycol group,represented by Formula (E)

wherein e is an integer from 1 to
 400. 20. The compound according toclaim 19, wherein R^(x) and R^(y) are each independently selected from—(O)CH₃, a guanidino group represented by Formula (A)

wherein a is an integer from 0 to 25, or a guanidinobenzene grouprepresented by Formula (C),

wherein c is an integer from 0 to
 25. 21. A pharmaceutical compositioncomprising a compound according to claim
 1. 22. The pharmaceuticalcomposition according to claim 21 for use in the treatment of oralmucositis.